Hepatic Mechanisms of Myocardial Infarction: A New Perspective in Metabolic Dysfunction‐Associated Fatty Liver Disease

Jing Cui; Wenting Wang; Qian Xu; Mengmeng Zhu; Yiwen Li; Yanfei Liu; Yue Liu

doi:10.1161/JAHA.124.040775

. 2025 Aug 29;14(17):e040775. doi: 10.1161/JAHA.124.040775

Hepatic Mechanisms of Myocardial Infarction: A New Perspective in Metabolic Dysfunction‐Associated Fatty Liver Disease

Jing Cui ¹, Wenting Wang ¹, Qian Xu ¹, Mengmeng Zhu ¹, Yiwen Li ¹, Yanfei Liu ^1,², Yue Liu ^1,^✉

PMCID: PMC12553439 PMID: 40879000

Abstract

Myocardial infarction is a major disease that seriously jeopardizes human health, and patients with comorbid metabolic disorders usually have a faster progression and worse prognosis. The presence of metabolic dysfunction‐associated fatty liver disease not only exacerbates insulin resistance and metabolic imbalance but also contributes to the progression of myocardial infarction in a multifaceted and multifaceted manner through interactions with peripheral adipose tissue, the intestinal microbiota, and epigenetic alterations, as well as “direct communication” between the heart and the liver. Both physiologically and pathologically, it is of interest to note that cross‐organ “direct communication” between the heart and the liver can occur in a variety of ways through a variety of means, including extracellular vesicles. In recent years, a variety of drugs with cardiovascular benefits have been found to treat metabolic dysfunction‐associated fatty liver disease, and the mechanisms are worth exploring. It is important to explore the hepatic mechanism of myocardial infarction from a new perspective of metabolic dysfunction‐associated fatty liver disease, which is centered on the imbalance of metabolic homeostasis and the process of heart–hepatic interorgan communication, for the prevention and treatment of cardiovascular diseases.

Keywords: metabolic disorders, metabolic dysfunction‐associated fatty liver disease, myocardial infarction, prevention and treatment strategies

Subject Categories: Metabolism, Cardiovascular Disease

Nonstandard Abbreviations and Acronyms

FGF21: fibroblast growth factor 21
GLP‐1 RA: glucagon‐like peptide‐1 receptor agonist
MAFLD: metabolic dysfunction‐associated fatty liver disease
SCFA: short‐chain fatty acid

A new definition of metabolic dysfunction‐associated fatty liver disease (MAFLD) was proposed in 2023, aiming to replace the previous terminology of nonalcoholic fatty liver disease. ¹ This new definition emphasizes the metabolic nature of the disease; highlights its association with obesity, type 2 diabetes, dyslipidemia, and other conditions; and is more practical for identifying patients at high risk for disease progression, comorbidities, and death. The global prevalence and mortality rates of MAFLD are increasing every year, and it has resulted in a significant disease burden. ² , ³ The newly released Asia‐Pacific Association for the Study of the Liver Clinical Practice Guideline: Diagnosis and Treatment of Metabolism‐Associated Fatty Liver Disease clearly states that MAFLD is one of the leading causes of liver disease worldwide, affecting more than one fourth of the world's adult population. Previous studies have found that MAFLD is strongly associated with the incidence of fatal and nonfatal cardiovascular disease (CVD) events. Patients with MAFLD have a significantly higher risk of CVD than those without MAFLD, and their risk is independent of conventional risk factors for CVD. ⁴ The overall prevalence of coronary heart disease was as high as 44.6% in patients with MAFLD. Further studies have shown that the severity of MAFLD is strongly associated with the severity of coronary artery obstruction in patients with acute coronary syndrome and that the prevalence of unstable coronary plaques is significantly higher in patients with MAFLD. Death from CVD due to myocardial infarction (MI) has become the leading cause of death in patients with MAFLD. ⁵

Metabolic dysfunction is a core driver of MAFLD and a key bridge for the progression of CVD to MI in patients with MAFLD. There is a complex interrelation between MAFLD and metabolic homeostasis. Abnormal lipid metabolism is a key pathological mechanism and initiating link in the formation and development of MAFLD. Adipokines, such as leptin and lipocalin, regulate the balance of local and systemic metabolic homeostasis in the liver, and excessive accumulation of lipids in the liver can directly induce the development of insulin resistance. ⁶ Increased visceral adipose tissue may be one of the distinctive hallmarks of MAFLD, ⁷ and visceral adipose tissue is likewise closely associated with hyperlipidemia and insulin resistance in patients with MAFLD. Conversely, chronic hyperglycemia can directly activate related genes such as carbohydrate response element binding protein, leading to a large accumulation of free fatty acids in hepatocytes and promoting the development of MAFLD ⁸ In addition to this, alterations in liver secreted proteins can independently affect cardiovascular health, such as SeP (selenoprotein P), adropin, fetuin‐A (fetal globulin A), fetuin‐B, and others.

It is thus clear that the management of MAFLD is not only necessary to directly reduce the risk of CVD but also an important part of metabolic management of the organism. Exploring the role played by MAFLD in the development of CVD and promoting early intervention is important for reducing the risk of MI and improving patient prognosis. This study systematically summarizes the current literature related to MAFLD and MI, with a view to providing some reference for the study of cardiovascular co‐morbidity in MAFLD.

METABOLIC HOMEOSTASIS IMBALANCE: A CRITICAL BRIDGE BETWEEN MAFLD AND MI

People with metabolic disorders have several times the risk of CVD than those without combined metabolic disorders, and the incidence of MI and the risk of death are significantly higher than those in the general population. ⁹ Atherosclerosis is the main pathological basis of MI, and its associated risk factors can accelerate the progression of MAFLD. The pathological mechanisms of MAFLD and atherosclerosis development are closely linked at multiple levels and ultimately lead to the development of MI (Figure 1).

Liver auto genes, insulin resistance, and lipid metabolism disorders appear to affect adipose tissue secretion disorders, peripheral inflammatory progression, and intestinal flora dysbiosis, exacerbating systemic metabolic disorders and leading to damage to both cardiac macrovessels and microvessels. CRP indicates C‐reactive protein; IL, interleukin; LPS, lipopolysaccharide; MCP, monocyte chemoattractant protein; NF‐κB, nuclear factor kappa B; TNF‐α, .tumor necrosis factor‐α; and VLDL, very low‐density lipoprotein cholesterol.

SIGNIFICANCE OF METABOLIC INFLAMMATION IN MAFLD AND MI

Studies have shown that the severity of MAFLD in patients with atherosclerotic CVD is strongly associated with the severity of coronary artery blockage. ¹⁰ Clinical data from 7761 participants in the NHANES III (third National Health and Nutrition Examination Survey) in the United States showed that patients with MAFLD had a nearly 25% higher risk of developing CVD than a group without MAFLD, and the incidence of MI was positively correlated with MAFLD severity. ¹¹ , ¹² Serum low‐density lipoprotein cholesterol level is one of the most important risk factors for MI. However, even when low‐density lipoprotein cholesterol is reduced to the recommended concentration, the residual risk of atherosclerotic CVD remains, and the reason for this may be closely related to lipid metabolism in the liver. For example, residual lipoprotein cholesterol secreted by the liver has been found to be an independent risk factor for MI. ¹³ The liver is the most important organ for lipid metabolism, and ectopic adipose tissue, such as myocardial fat and pericardial adipose tissue, is closely related to fat accumulation in the liver and is central to the relationship between MAFLD and CVD. It has been demonstrated that epicardial fat accumulation is strongly associated with MI in the general population and is independent of traditional cardiovascular risk factors. ¹⁴ In patients with MAFLD, systemic inflammatory syndromes lead to abnormal activation of adipocytes and secretion of proinflammatory factors, which promote myocardial inflammation and MI. ¹⁵ Metabolic disorders can induce inflammation, and inflammatory mediators themselves can trigger metabolic changes. ¹⁶ Insulin resistance can alter systemic lipid metabolism, induce endothelial dysfunction, and promote atherosclerosis plaque formation. Reducing insulin resistance may help to reduce the generation of coronary heart disease and atherosclerosis plaques, thus reducing the risk of MI. This shows that insulin resistance, lipid metabolism, and inflammation are important factors linking MAFLD and MI.

CYTOKINES AND EXTRACELLULAR VESICLES MEDIATE DIRECT “HEART–LIVER” DIALOGUE IN MAFLD AND MI

An increasing number of studies have observed close communication between the heart and the liver in pathological states. FGF21 (fibroblast growth factor 21) has been shown to mediate heart‐hepatic communication during MI. It has been found that MI‐induced production of IL‐6 (interleukin‐6) inhibits MR (mineralocorticoid receptor) expression through activation of STAT3 (signal transducers and activators of transcription 3) protein in the liver. MR negatively regulates hepatic FGF21 expression by binding to nuclear receptor corepressor 1 and histone deacetylase 3 in hepatocytes, which in turn promotes cardiac repair and inhibits cardiac remodeling after MI in an endocrine manner. ¹⁷ FGF21 is able to attenuate inflammation and oxidative stress through activation of the Nrf1 pathway ¹⁸ and also inhibits apoptosis induced by lipids or diabetes in cardiomyocytes through the ERK1/2)‐p38 MAPK‐AMPK (extracellular regulated kinase 1/2‐p38 mitogen‐activated protein kinase‐adenosine 5′‐monophosphate‐activated protein kinase) pathway. Further studies found that overexpression of sirtuin 5 in the liver promoted the secretion of FGF21 into the bloodstream in the liver after MI, improved cardiomyocyte energy metabolism, and reduced myocardial injury and myocardial fibrosis after MI. ¹⁹ Gp130, a molecule that is closely related to tissue regeneration, is involved in both hepatic and cardiac organ repair processes, involving very different pathways. Hepatic Kupffer cells specifically produce IL‐6, which induces hepatocyte reprogramming through Gp130 and promotes hepatocyte regeneration through JAK (Janus kinase)/STAT3. ²⁰ In myocardial tissues, macrophages can activate cardiomyocyte Gp130 receptors through secretion of oncostatin M, activate the Yap‐Src nonclassical cell proliferation pathway, and promote cardiomyocyte proliferation. ²¹ Another study found that steatotic hepatocyte‐derived extracellular vesicles exacerbated foam cell formation and atherosclerosis progression by inhibiting macrophage reverse cholesterol transport via the miR‐30a‐3p/ABCA1 (adenosine‐5′‐triphosphate ‐binding cassette transporter A1) pathway. ²²

BIDIRECTIONAL ROLE OF GUT MICROBIOTA IN MAFLD AND MI

In recent years, the relationship between the gut microbiota and metabolic diseases has been intensively studied. Imbalances in the gut microbiota increase the risk of metabolic diseases such as obesity, diabetes, and MAFLD. ²³ Altered bacterial ratios and dysregulated metabolites in the gut microbiota lead to increased intestinal permeability and systemic inflammation, which promotes the development of MAFLD and atherosclerosis and is an important risk factor for the development of MI. ²⁴ , ²⁵

Previous studies have shown that patients with MAFLD have diminished hepatic metabolic function and elevated serum endotoxin levels, which activate inflammatory pathways and lead to disruption of the intestinal epithelial barrier and the intestinal vascular barrier. ²⁶ The intestinal microbiota translocates to the liver and blood, inducing systemic immune inflammation and promoting the development of atherosclerosis and MI. ²⁷ , ²⁸ A large sample of patients with MAFLD was analyzed histologically to identify 2 main MAFLD subtypes, of which one of the distinctive features of the cardiometabolic type is the increased concentration of several gut microbiota metabolites. ²⁹

On the other hand, dysregulation of metabolites in the gut microbiota can exacerbate the development of MAFLD and atherosclerosis. Short‐chain fatty acids (SCFAs) and bile acids are the main metabolites of the gut microbiota. Gut microbes influence lipid absorption and cholesterol metabolism by regulating bile acid metabolism. Under conditions of microbiota dysregulation, bile acid levels are elevated, interacting with farnesoid X receptor in the gut, and hepatic lipogenesis, metabolism, and inflammatory regulation are limited. ³⁰ SCFAs are not only able to regulate fatty acid synthesis and catabolism by acting on GPR41 (G‐protein receptor 41) and GPR43 receptors but can also affect lipid storage and fatty acid oxidation. ³¹ Acetic, propionic, and butyric acid contents account for >95% of the total gut‐derived SCFAs content. In general, butyrate attenuates the host inflammatory response by activating the TLR4 (toll‐like receptor 4) pathway, enhancing the anti‐inflammatory properties of macrophages and dendritic cells, and inducing IL‐10 production and differentiation of regulatory T cells. Butyrate is also able to promote fatty acid oxidation and inhibit lipid synthesis by activating the AMPK signaling pathway, thus helping to maintain the balance of lipid metabolism. ³² In a state of microbiota dysbiosis, intestinal SCFAs are reduced, the energy supply of intestinal epithelial cells is insufficient, and the intestinal barrier is further disrupted. ³³ Trimethylamine oxide is ultimately formed in the liver and is a recognized risk factor for several CVDs including MI. In contrast, phenylacetylglutamine promotes platelet activation‐related phenotypes and has been shown to be associated with MI in large independent cohorts. ³⁴

ROLE OF PROTEIN METABOLISM IN MAFLD AND MI

The liver is a key organ for protein synthesis and degradation, and protein synthesis, degradation, and amino acid metabolism are all altered to some extent in the MAFLD state, thus affecting the development of MI (Figure 2). For the liver itself, the main aspects involved are regulation of lipid metabolism, modulation of inflammation and improvement of fibrosis.

Hepatic genetic variation affects atherosclerosis and endothelial cells by altering glucolipid metabolism and inflammatory responses; several secreted proteins of the liver can directly influence the atherosclerotic process. AMPK indicates adenosine 5′‐monophosphate‐activated protein kinase; BMP7, bone morphogenetic protein 7; MMP2, matrix metallopeptidase 2; PAI‐1, plasminogen activator inhibitor‐1; SDF‐1, stromal cell‐derived factor 1; TGF‐β, transforming growth factor‐β; and VSMC, vascular smooth muscle cell.

Regarding the regulation of lipid metabolism, the hepatocyte‐derived secreted protein Lcn2 inhibits the atherosclerosis process in mice by decreasing Nedd4‐1‐mediated ubiquitination of the cell membrane receptor SR‐BI (scavenger receptor group B type 1) K500 and K508 sites, blocking SR‐BI degradation, and facilitating reverse cholesterol transport. ³⁵ Similarly, the hepatocyte transcription factor ATF3 (activating transcription factor 3) enhances the promoter activity of SR‐BI via p53, initiates the reverse cholesterol transport process and inhibits small intestinal fat and cholesterol absorption, and its inhibition of the atherosclerosis process is independent of apoE (apolipoprotein E) and low density lipoprotein receptor. ³⁶ The KLF (Krüppel ‐like factor) family is closely related to lipid metabolism, and knockdown of the cardiac Klf15 gene promotes adiposity and lipid accumulation in hepatic tissues, and small leucine rich protein 1 gene deletion similarly occurs. ³⁷ , ³⁸ LXRα (liver X receptor α) is not only an important factor in maintaining normal cholesterol transport, but LXRα deficiency also leads to impaired glucose metabolism, increased infarct size, and worsened myocardial fibrosis. ³⁹ Activation of farnesoid X receptor in the liver and intestinal farnesoid X receptor deficiency both inhibit atherosclerosis development, ⁴⁰ , ⁴¹ and cardiac lipid accumulation is more pronounced in farnesoid X receptor knockout mice. ⁴²

MAFLD‐associated hepatic fibrosis and chronic inflammation are both associated with higher risk of cardiovascular disease and mortality. Elevated levels of FIB‐4 were independently associated with MI in patients with type 2 diabetes. FSTL3 (follistatin‐like protein 3) was enriched in the livers of patients with MAFLD with significant and advanced fibrosis, and serum FSTL3 partially mediated the association of increased risk of hepatic fibrosis with patients with type 2 diabetes association of increased risk with MI. Macrophage apoptosis inhibitory factor exerts a protective effect against hepatic fibrosis through multiple mechanisms ⁴³ , ⁴⁴ ; however, deletion of apoptosis inhibitory factor reduces the incidence of cardiac rupture and decreases acute infarct size after MI in mice. ⁴⁵ Elevated expression of proline and arginine‐rich end leucine‐rich repeat protein promotes cardiac and hepatic fibrosis as well as chronic inflammation, and knockdown significantly alleviates fibrosis.

The liver produces a number of secreted proteins that can independently affect the atherosclerotic process and cardiac function. SeP synthesized and released by the liver has been found to inhibit cell proliferation and impair angiogenesis, and inhibition of SeP protects the heart from ischemia/reperfusion injury by upregulating the reperfusion injury salvage kinase pathway. ⁴⁶ Adropin inhibits angiotensin II‐induced proliferation and phenotypic modulation of vascular smooth muscle cells through AMPK/acetyl‐coA carboxylase signaling, inhibits TNF‐α (tumor necrosis factor‐α)‐induced THP1 monocyte adhesion to vascular endothelial cells, preventing macrophage polarization, and attenuating atherosclerosis in mice through TGF‐β (transforming growth factor‐β)/Smad2/3 signaling pathway. ⁴⁷ Fetuin‐A independently inhibits calcification of atherosclerosis plaques. ⁴⁸ Circulating fetuin‐B levels are elevated in patients with acute MI, and fetuin‐B increases migration of mouse monocytes and macrophages, stimulates stromal cell‐derived factor‐1 production in vascular smooth muscle cells, and promotes plaque rupture by inducing plasminogen activator inhibitor‐1 and matrix metallopeptidase 2 expression in vascular smooth muscle cells via TGF‐β receptor/Smad signaling. ⁴⁹ Fetuin‐B elevated levels can also lead to inhibition of cardiac insulin‐induced signaling and exacerbate myocardial ischemia/reperfusion injury. ⁵⁰ Coagulation factor XII is able to mediate endothelial dysfunction, vascular inflammation, and atherosclerosis. ⁵¹ Recent studies have found that coagulation factor XI is able to inhibit inflammation and fibrosis and prevent cardiac diastolic dysfunction through cleavage of BMP7 (bone morphogenetic protein 7) precursors and activation of the BMP7‐SMAD1/5 pathway. ⁵²

It can be seen that a variety of proteins synthesized and metabolized by the liver play an important role in the development and progression of MI and in the interaction between MAFLD and MI.

THE ROLE OF GENETIC FACTORS IN MAFLD AND MI

Genetic polymorphisms and susceptibility also play an important role in the association between MAFLD and CVD. Rs738409 polymorphism in the PNPLA3 gene, known as the PNPLA3 I148M (PNPLA3 rs738409 C>G) variant, has been found to be one of the determining genetic factors for MAFLD and is strongly associated with MAFLD morbidity and mortality. ⁵³ This genetic variant exacerbates the progression of fat accumulation, steatohepatitis, and hepatic fibrosis mainly by affecting lipid metabolism and promoting inflammatory responses. ⁵⁴ Carrying the PNPLA3 I148M variant reduces the risk of cardiovascular mortality although it increases overweight/obesity and liver‐specific mortality. ⁵⁵ , ⁵⁶ , ⁵⁷ The mechanism may be related to the fact that PNPLA3‐I148M has antiatherosclerosis lipid properties. Studies have shown that the PNPLA3‐I148M protein in the liver decreases very low‐density lipoprotein and low‐density lipoprotein particles and increases high‐density lipoprotein particles, thereby exerting cardioprotective effects. ⁵⁸ Similarly, the TM6SF2 genetic variant can prevent CVD by reducing lipoprotein secretion while causing metabolic dysfunction‐associated steatohepatitis. ⁵⁹

In addition, gender differences are equally noteworthy. The polygenic risk score for MAFLD showed different trends in liver‐related diseases such as hepatocellular carcinoma due to gender. ⁶⁰ Sex hormones are able to influence the entire process of MAFLD, including metabolism, oxidative stress, immune response, and tissue regeneration. Estrogen deficiency in postmenopausal women promotes proinflammatory responses and oxidative stress, exacerbating inflammation and MAFLD progression. Estrogen replacement reduces hepatic fat deposition by enhancing insulin sensitivity and inhibiting fat synthesis. Estrogen treatment reversed hepatic steatosis and restored hepatic lipid metabolism in aromatase‐knockout male mice. ⁶¹ In the liver, estrogen acts mainly through Er‐α (estrogen receptor‐α). The genetic variant of PNPLA3 p.I148M has a clear role in increasing the risk of MAFLD in women, especially in postmenopausal women, and the main mechanism may be that estrogen induces an upregulation of PNPLA3 expression through ER‐α leading to hepatocellular fat accumulation. ⁶² The role of androgen signaling in MAFLD may be controversial, with androgen deficiency leading to hepatic steatosis, although testosterone supplementation can reverse this phenomenon. ⁶³ However, exogenous androgen supplementation not only leads to liver damage in men but also exacerbates the risk of MAFLD in women. ⁶⁴ , ⁶⁵

CORRECTING METABOLIC DISORDERS: “COBENEFITS” FOR HEART AND LIVER

For the prevention and treatment of MAFLD, updated guidelines have been proposed by the American Association for the Study of Liver Diseases (2023), ⁶⁶ and the European Association for the Study of the Liver (2024). ⁶⁷ The management of MAFLD is mainly characterized by lifestyle interventions such as control of caloric intake and moderate‐intensity exercise. In terms of pharmacological interventions, recently the Food and Drug Administration of the United States approved for the first time the marketing of Resmetirom, an oral selective agonist of thyroid hormone receptor β targeting the liver, which was able to significantly improve the manifestations of fatty liver pathology in patients, as well as lowering cardiovascular health‐related markers such as low‐density lipoprotein cholesterol, and demonstrated a favorable safety profile. ⁶⁸

Measures to help improve the prevention of MI in atherosclerosis, such as the use of lipid‐lowering medications, are equally beneficial in slowing the progression of MAFLD. Studies have noted that statins reduce the risk of MAFLD in patients with hypercholesterolemia. ⁶⁹ A meta‐analysis further confirmed that statins significantly improved liver function and dyslipidemia in patients with MAFLD. ⁷⁰ Compared with nonusers, people using statins had reduced risk of developing hepatocellular carcinoma in MAFLD, and the reduction in harm was greater as the dose and duration of statin use increased. ⁷¹ The mechanism can be related to the inhibition of hepatic fibrosis by statins in addition to the lipid‐lowering effect. A nested case–control study that included 200 000 Asian individuals showed that statin therapy reduced the risk of CVD in patients with a high fatty liver index MAFLD but not in those with a low fatty liver index. ⁷² However, due to the greater metabolic burden of statins on the liver, the safety of using this class of drugs for the treatment of MAFLD and its risk for the occurrence of MI in the long term is still subject to further study. ⁷³ PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors, with their favorable lipid‐lowering effects, are one of the good medication choices for patients with atherosclerotic CVD and have been found to be effective in decreasing the risk of MI in patients with metabolic diseases. ⁷⁴ A clinical study that included 110 subjects showed that the expression of PCSK9 in the liver was significantly elevated in patients with MAFLD, and the serum concentration of PCSK9 was more likely to be related to the cholesterol levels of patients. ⁷⁵ A network analysis by Swedish scholars showed that PCSK9 expression was significantly upregulated in patients presenting with elevated lipogenic enzyme expression. ⁷⁶ Further experimental studies confirmed that PCSK9 knockdown was able to exacerbate diet‐induced MAFLD and metabolic dysfunction‐associated steatohepatitis in mice, a result that suggests a potential role for PCSK9 in preventing hepatic steatosis and liver injury. ⁷⁷ In addition, PCSK7 targets may be promising potential targets for MAFLD treatment and are able to synergize with PCSK9. ⁷⁸ However, it is worth noting that the clinical efficacy and safety of PCSK9 inhibitors for the treatment of MAFLD still need to be interpreted with caution, as there is a considerable paucity of large randomized controlled studies of PCSK9 inhibitors for the treatment of MAFLD.

In contrast to lipid‐lowering agents, newer glucose‐lowering agents that are widely used are favored not only for their cardiovascular benefits, but also for their hepatoprotective effects that have been confirmed in several studies, including glucagon‐like peptide‐1 receptor agonists (GLP‐1 RA), dipeptidyl peptidase‐4 inhibitors, and sodium‐glucose cotransporter protein‐2 inhibitors. Relevant completed and ongoing clinical studies in the clinical trials registry platform (https://www.clinicaltrials.gov/) are listed in Tables 1 and 2.

Table 1.

Completed Clinical Trials for GLP‐1 RA, DPP‐4i, and SGLT‐2i on MAFLD

Clinical trial title	NCT Number	Condition	Intervention	Primary outcome	Cardiovascular indicators	Duration	Country
Effect of Dulaglutide on Liver Fat in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease (D‐LIFT)	NCT03590626	MAFLD, T2D	Dulaglutide	Change in liver fat quantified by MRI‐PDFF in colocalized regions of interest	Interleukin‐1, tumor necrosis factor‐α, hs‐CRP, leptin, adiponectin, and homocysteine	0.75 mg weekly/4 wks, 1.5 mg weekly/20 wks	India
Adding Exenatide to Insulin Therapy for Patients With Type 2 Diabetes and Non‐Alcoholic Fatty Liver Disease	NCT01006889	MAFLD, T2D	Exenatide	Determine the impact on hepatic steatosis of replacing premeal rapid‐acting insulin for exenatide (Byetta) while maintaining bedtime long‐acting detemir (Levemir) insulin	hsCRP, intercellular adhesion molecule, vascular cell adhesion molecule	2 y	United States
A Study of Efinopegdutide (MK‐6024) in Participants With Nonalcoholic Fatty Liver Disease (NAFLD) (MK‐6024‐001)	NCT04944992	MASH/MAFLD	Efinopegdutide 20 mg/mL; Semaglutide 1.34 mg/mL	Liver fat reduction assessed by MRI‐PDFF	/	24 wks	United States
Novel Antidiabetic Medications and Their Effect on Liver Steatosis (NAMELS‐18)	NCT05946148	MAFLD, liver steatosis	Empagliflozin; dulaglutide	Liver steatosis change	/	52 wks	Greece
Effects of Exenatide (Byetta) on Liver Function in Patients With Nonalcoholic Steatohepatitis (NASH)	NCT01208649	MAFLD	Exenatide	Biochemical and histological parameters of liver function by liver biopsies and magnetic resonance tomography	/	24 wks	Germany
Study of Semaglutide for Non‐Alcoholic Fatty Liver Disease (NAFLD), a Metabolic Syndrome With Insulin Resistance, Increased Hepatic Lipids, and Increased Cardiovascular Disease Risk (The SLIM LIVER Study)	NCT04216589	HIV infections, MAFLD	Semaglutide	Intrahepatic triglyceride content, quantified by MRI‐PDFF	/	24 wks	United States
A Study on How Semaglutide Works on Early Stages of Scar Tissue in the Liver Assessed by Pictures of the Liver	NCT03357380	Hepatobiliary disorders, MAFLD	Semaglutide, placebo	Liver fibrosis assessed by magnetic resonance elastography	/	72 wks	Novo Nordisk
Semaglutide in Nonalcoholic Fatty Liver Disease	NCT05813249	MAFLD	Rybelsus oral/Ozempic injectable semaglutide; Tocopherol or actos	Improvement in liver stiffness and severity of hepatic steatosis	/	48 wks	Egypt
Safety, Tolerability, and Efficacy of Monotherapy and Combination Regimens in Participants With Nonalcoholic Steatohepatitis (NASH)	NCT03987074	MASH	Semaglutide; firsocostat; cilofexor	Evaluate the safety and tolerability of semaglutide	/	1 y	Gilead Sciences/United States
Role of Exenatide in NASH‐a Pilot Study (NAFLD)	NCT00650546	MAFLD	Exenatide	Improvement of liver histology, accessed by nonalcoholic fatty liver disease activity score live biopsy	/	24–28 wks	United States
Exenatide Compared With Insulin Glargine to Change Liver Fat Content in Type 2 Diabetes	NCT02303730	T2D, MAFLD	Exenatide, insulin glargine	Evaluate whether exenatide is superior to insulin glargine (after 24 wks) in reducing liver fat content (by MRS)	/	24 wks	China
Antidiabetic Effects on Intrahepatic Fat	NCT03068065	T2D, MAFLD	Liraglutide, metformin, gliclazide	Comparison of efficacy by quantitative ultrasonography	/	24 wks	China
Efficacy Study of Liraglutide vs Sitagliptin vs. Glargine on Liver Fat in T2DM Subjects (LIGHT‐ON)	NCT02147925	MAFLD	Liraglutide+metformin; insulin glargine+metformin; sitagliptin+metformin	Compare the change of IHL as measured by MRI‐PDFF as measured by iterative decomposition of water and fat with echo asymmetry and least‐squares estimation	/	26 wks	China
Liraglutide Efficacy and Action in Non‐Alcoholic Steatohepatitis (LEAN)	NCT01237119	MAFLD, overweight	Liraglutide; placebo	Improvement in histological disease activity by liver biopsy	/	48 wks	Britain
Study of Liraglutide Versus Insulin on Liver Fat Fraction in Patients With Type 2 Diabetes (LIRAINS)	NCT01399645	MAFLD, T2D	Liraglutide‐metformin; insulin‐metformin	Improvement in steatosis of 5% before and after treatment	/	12 wks	Canada
Non‐Alcoholic Fatty Liver Disease and Its Treatment	NCT05480007	MAFLD	Sitagliptin and metformin; sitagliptin; metformin	Ability of DPP‐4I to improve IHL content was measured by using 1H‐MRS quantitative detection	/	24 wks	China
Sitagliptin Versus Placebo in the Treatment of Non‐alcoholic Fatty Liver Disease	NCT01963845	MAFLD	Sitagliptin, placebo	Improvement in hepatic steatosis measured by MRI	/	24 wks	United States
Role of Vitagliptin and Vitamin D in the Treatment of Non Alcoholic Fatty Liver Disease (NAFLD)	NCT01083992	MAFLD	Vitagliptin, vitagliptin+ vitamin D	Improve the histopathology findings in MAFLD	/	24 wks	Israel
Anti‐diabetic Drugs and Fatty Liver Management	NCT05041673	T2D, MAFLD	Vildagliptin, liraglutide, and empagliflozin	Improvement in hepatic steatosis measured by MRI	/	1 y	Egypt
To Evaluate the Effect of Nesinaact on Non‐alcoholic Steatohepatitis Through MRI and Liver Fibroscan in Patients With Type 2 Diabetes	NCT03950505	MAFLD, T2D	Alogliptin benzoate 25 mg, pioglitazone hydrochloride 15 mg	Effect of nesinaact on nonalcoholic steatohepatitis through MRI and liver fibroscan	/	24 wks	South Korea
Dapagliflozin Efficacy and Action in NASH (DEAN)	NCT03723252	MASH	Dapagliflozin, placebo	Efficacy and safety of dapagliflozin on improving nonalcoholic steatohepatitis as determined by liver biopsies	/	/	China
Effect of Empagliflozin on Liver Fat in Non‐diabetic Patients	NCT04642261	MAFLD	Empagliflozin 10 mg, placebo pills	Difference in change of liver fat content (measured by MRI‐PDFF) at wk 52 from baseline	/	52 wks	Hong Kong
Comparison of The Effects of Thiazolidinediones (TZD), Sodium‐ Glucose Cotransporter 2 Inhibitors (SGLT2i) Alone and TZD /SGLT2i Combination Therapy on Non‐alcoholic Fatty Liver Disease in Type 2 Diabetic Patients With Fatty Liver	NCT03646292	MAFLD, T2D	Empagliflozin 10 mg+pioglitazone 15 mg	Difference of liver fat change measured by MRI‐PDFF in colocalized regions of interest within 9 liver segments	/	6 mo	South Korea
Effect of Empagliflozin on Liver Fat Content in Patients With Type 2 Diabetes (E‐LIFT)	NCT02686476	MAFLD	Empagliflozin	Evaluate the change in liver fat content from baseline at week 12 by MRI‐PDFF	/	12 wks	India
Effect of Oral Anti‐diabetic Medication on Liver Fat in Subjects With Type II Diabetes and Non‐alcoholic Fatty Liver	NCT04976283	T2D, MAFLD	Pioglitazone, empagliflozin, pioglitazone + empagliflozin	Effect of SGLT inhibitor with or without metformin and/or DPP4 inhibitor (no pioglitazone) on MAFLD parameters	/	/	Pakistan
Novel Antidiabetic Medications and Their Effect on Liver Steatosis (NAMELS‐18)	NCT05946148	MAFLD, liver steatosis	Empagliflozin, dulaglutide, control Rx	Determine percentage of those with >30% liver fat concentration reduction by abdominal ultrasound, magnetic resonance imaging‐proton density fat fraction, shear wave elastography	/	52 wks	Greece

Open in a new tab

The table content is sourced from the ClinicalTrials.gov. DPP‐4i, indicates dipeptidyl peptidase—4 inhibitor; GLP‐1 RA, glucagon‐like peptide‐1 receptor agonist; hs‐CRP, c‐reactive protein; IHL, intrahepatic lipids; MASH, metabolic associated steatohepatitis; MAFLD, metabolic associated fatty liver disease; MRI‐PDFF, magnetic resonance imaging‐proton density fat fraction; MRS, magnetic resonance spectroscopy; NCT, National Clinical Trials; SGLT‐2i, sodium‐glucose cotransporter protein‐2 inhibitors; and T2DM, type 2 diabetes.

Table 2.

Ongoing Clinical Trials for GLP‐1 RA, DPP‐4i, SGLT‐2i on MAFLD

Clinical trial title	NCT Number	Condition	Intervention	Primary outcome	Cardiovascular indicators	Duration	Country
Dapagliflozin in Type 2 Diabetes Mellitus Patients (T2DM) With Nonalcoholic Fatty Liver Disease (NAFLD)	NCT05459701	MAFLD, T2D	Dapagliflozin 10 mg tablet	Liver function, alanine aminotransferase, aspartate aminotransferase	Vascular cell adhesion molecule‐1	2 y	Egypt
MASLD in Primary Hypothyroidism and Efficacy of Dapaglifozin (SHIELD)	NCT06373523	Hepatic steato‐fibrosis, MAFLD	Dapagliflozin 10 mg tablet, placebo, levothyroxine replacement daily	Difference in change of liver fat content (measured by MRI‐proton density fat fraction) at wk 28	Cardiovascular events at wk 14 and 28	28 wks	India
Researching the Effect of GLP‐1 Agonist on Liver STeatosis (REALIST)	NCT03648554	T2D, MASH	Dulaglutide 1.5 mg	Histological improvement (based on NAS) without worsening of fibrosis (based on liver biopsy)	/	Treatment: 52 wks; follow‐up: 24 wks	France
Effect of Empagliflozin and Dulaglutide on MAFLD in Patients With T2D	NCT05140694	MAFLD, T2D	Empagliflozin and Dulaglutide	Hepatic steatosis estimated by fibroscan	/	2 y	Korea
Non‐Alcoholic Fatty Liver Disease, the Hepatic Response to Oral Glucose, and the Effect of Semaglutide (NAFLD HEROES)	NCT03884075	MASH/MAFLD	Semaglutide	Histological improvement (based on NAS)/clinical improvement/change in hepatic gene expression	/	30 wks	United States
Research Study on Whether Semaglutide Works in People with Non‐alcoholic Steatohepatitis (NASH)	NCT04822181	MASH	Semaglutide	Resolution of steatohepatitis and no worsening of liver fibrosis (based on NAS)/improvement in liver fibrosis and no worsening of steatohepatitis (based on NAS)/iime to first liver‐related clinical event	/	72 wks/72 wks/240 wks	United States
Semaglutide Treatment in the Real‐world for Fibrosis Due to NAFLD in Obesity and T2DM (SAMARA)	NCT06005012	T2D, MAFLD	Semaglutide	Significant fibrosis due to MAFLD	/	2 y	United States
Semaglutide Effects in Obese Youth With Prediabetes	NCT05067621	T2D, MAFLD, obesity, childhood	Semaglutide, 2.4 mg, once weekly	Beta‐cell preservation and reduction of intrahepatic triglyceride content in obese youth	/	6 mo	United States
Effect on Non‐Alcoholic Fatty Liver Disease in Patients With Type 2 Diabetes Mellitus With Gastric Inhibitory Polypeptide/Glucagon Like Peptide‐1 Analogue	NCT05751720	MAFLD, T2D	Subcutaneous tirzepatide or oral Semaglutide	Reduction in liver fat accessed by fibroscan or MRI fat measurement	/	6 mo	United Arab Emirates
A Clinical Study of Efinopegdutide in Participants With Precirrhotic Nonalcoholic Steatohepatitis (NASH) (MK‐6024‐013)	NCT05877547	MAFLD	Efinopegdutide, semaglutide, placebo	Safety and benefit of efinopegdutide	/	/	Merck Sharp & Dohme LLC/ United States
Combined Active Treatment in Type 2 Diabetes With NASH (COMBAT_T2_NASH)	NCT04639414	MAFLD, T2D	Empagliflozin 10 mg oral tablet/semaglutide 1 mg pen injector	Histological resolution by liver biopsy	/	48 wks	Germany
Research Study on Whether a Combination of 2 Medicines (NNC0194 0499 and Semaglutide) Works in People With Non‐alcoholic Steatohepatitis (NASH)	NCT05016882	MASH	Semaglutide 3 mg/mL; NNC0194 0499 50 mg/mL; placebo	Reduction of liver damage by liver biopsies	/	19 mo	Novo Nordisk/ United States
Effects of GLP‐1RA on Body Weight, Metabolism and Fat Distribution in Overweight/ Obese Patients With Type 2 Diabetes Mellitus	NCT05779644	Obesity, T2D, MAFLD	Liraglutide, semaglutide, metformin	Changes of lipid metabolism and fat distribution in patients with overweight/obesity with type 2 diabetes	/	1 y	China
Study to Evaluate the Efficacy and Safety of DA‐1241 in Subjects With Presumed NASH	NCT06054815	MASH	DA‐1241, sitagliptin, DA‐1241 placebo, sitagliptin placebo	Evaluate the efficacy and safety of DA‐1241	/	16 wks	NeuroBo Pharmaceuticals Inc/United States
Efficacy and Safety of Dapagliflozin in Patients With Non‐alcoholic Steatohepatitis	NCT05254626	MASH	Dapagliflozin 10 mg tablet, pioglitazone 30 mg	Improvement of NAS by liver biopsy	/	24 wks	Egypt
A Single Center, Randomized, Open Label, Parallel Group, Phase 3 Study to Evaluate the Efficacy of Dapagliflozin in Subjects With Nonalcoholic Fatty Liver Disease	NCT05308160	Fatty liver	Dapagliflozin 10 mg yab, placebo	Efficacy of dapagliflozin in subjects with nonalcoholic fatty liver disease	/	/	Taiwan
Efficacy of Canagliflozin Versus Metformin in Women With Polycystic Ovary Syndrome	NCT06256289	Polycystic ovary syndrome, MAFLD	Canagliflozin 100 mg tablet, metformin hydrochloride	Noninvasive hepatic fat changes, metabolomics, and MAFLD‐related indicators, menstrual patterns, anthropometric parameters, gonadal parameters, glucose‐lipid homeostasis, liver enzyme indices	/	3 mo	China
Canagliflozin on Liver Inflammation Damage in Type 2 Diabetes Patients With Nonalcoholic Fatty Liver Disease	NCT05513729	T2D with complication	Canagliflozin, pioglitazone	Plasma cholesteryl ester transfer protein concentration and activity, as measurements of liver lipid content, hepatic steatosis, liver inflammation and damage	/	24 wks	China
SGLT2 Inhibitors as a Novel Treatment for Pediatric Non‐Alcoholic Fatty Liver Disease (SLIDE)	NCT03867487	Pediatric MAFLD	Empagliflozin 10 mg, placebo oral tablet	Efficacy and safety of SGLT2 inhibitors	/	/	United States
Efficacy of Empagliflozin and Pioglitazone in Diabetic Patients With NAFLD	NCT05942963	MAFLD, T2D	Empagliflozin 10 mg, pioglitazone 15 mg, metformin	Efficacy of empagliflozin by	/	/	Pakistan
Comparative Clinical Study Between Empagliflozin Versus Pioglitazone in Non‐diabetic Patients With Non‐alcoholic Steatohepatitis	NCT05605158	MASH	Empagliflozin 10 mg, pioglitazone 30 mg	Change in fibrosis indices (fibrosis‐4 and aspartate aminotransferase to platelet ratio index) and the liver enzymes	/	24 wks	Egypt
Combined Active Treatment in Type 2 Diabetes With NASH (COMBAT_T2_NASH)	NCT04639414	T2D, MASH, MAFLD	Empagliflozin 10 mg oral tablet/semaglutide 1 mg pen injector	Efficacy evaluated by means of histological resolution	/	48 wks	Germany

Open in a new tab

The table content is sourced from the ClinicalTrials.gov. DPP‐4i indicates dipeptidyl peptidase‐4 inhibitor; GLP‐1 RA, glucagon‐like peptide‐1 receptor agonist; MASH, metabolic associated steatohepatitis; MAFLD, metabolic associated fatty liver disease; MRI, magnetic resonance imaging; MRI‐PDFF, magnetic resonance imaging‐; NAS, nonalcoholic fatty liver disease activity score; NCT, National Clinical Trials; SGLT2, sodium‐glucose co‐transporter 2; and T2D, type 2 diabetes.

Compared with metformin or other glucose‐lowering agents, patients with both MAFLD and type 2 diabetes taking GLP‐1 RA had lower rates of MI and all‐cause mortality. ⁷⁹ Another study found that GLP‐1 RA intervention significantly improved hepatic steatosis and reduced the risk of metabolic dysfunction‐associated steatohepatitis and MI in patients. ⁸⁰ , ⁸¹ The incidence of MI was significantly reduced in patients treated with liraglutide in the LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) trial, which enrolled 9340 patients. ⁸² Similar studies have likewise confirmed the efficacy and safety of GLP‐1 RAs such as semaglutide, dulaglutide, and albiglutide in the risk of MI in patients with MAFLD. ⁸³ , ⁸⁴ The effects of GLP‐1 RAs on reducing body weight and increasing insulin sensitivity may be an important mechanism of their amelioration of MAFLD. In addition, its protective effect on MAFLD may be related to the regulation of hepatic fatty acid oxidation, inhibition of NLRP3 inflammasome‐mediated oxidative stress and cell death. ⁸⁵ , ⁸⁶ Dipeptidyl peptidase‐4 inhibitors significantly reduce the incidence of MI and the risk of all‐cause mortality, improves insulin resistance, reduces inflammasome response, and exerts a cardiovascular protective effect in patients with type 2 diabetes. Clinical trials have demonstrated that selegiline improves MAFLD and metabolic dysfunction‐associated steatohepatitis by mechanisms involving inhibition of hepatic oxidative stress and inflammatory processes. ⁸⁷ , ⁸⁸ In patients with MAFLD combined with type 2 diabetes with poor glycemic control, selegiline in combination with metformin was able to reduce intrahepatic lipid accumulation and hepatic function. ⁸⁹ The mechanisms by which sodium‐glucose cotransporter protein‐2 inhibitor analogs improve CVD outcomes mainly involve glucose‐lowering, inhibition of inflammation, and imbalance of myocardial energy supply and demand. ⁹⁰ Studies have confirmed that engeletin intervention promotes autophagy, reduces endoplasmic reticulum stress, inhibits hepatocyte apoptosis, and attenuates MAFLD progression in apoE mice. ⁹¹ Dagliflozin was able to inhibit myocardial fibrosis after MI in rats and was able to significantly inhibit LXRα‐mediated lipid de novo synthesis and bile acid synthesis, effectively attenuating liver injury. ⁹² Overall, novel hypoglycemic agents may have some synergistic effects in improving MAFLD and reducing the risk of MI occurrence. However, their true efficacy and safety still need to be verified in large‐sample randomized controlled studies.

Dietary interventions can work together to improve heart and liver function, prevent MAFLD and atherosclerotic CVD, and reduce inflammation and MI. Studies have found that high‐fat diets affect the composition of the gut microbiota. A diet high in saturated fat not only promotes the growth of proinflammatory bacterial communitie, but also suppresses probiotic populations, leading to an imbalance in the gut microbiota. ⁹³ Unsaturated fatty acids, such as omega‐3 fatty acids, ameliorate fat accumulation in the liver through anti‐inflammatory effects and help regulate blood lipid levels. ⁹⁴ Patients with obesity have a reduced diversity of gut microbiota, and specific microbial communities may promote fat storage and insulin resistance, whereas probiotics are able to ameliorate hepatic fat accumulation and enhance insulin sensitivity through modulation of SCFAs in the gut, which in turn improves metabolic status. ⁹⁵ In addition, Saskatoon berries (Amelanchieralnifolia), have been shown to improve cardiac and hepatic structure and function, reduce inflammatory cell infiltration, and lower total plasma cholesterol. ⁹⁶ Apigenin supplementation prevented atherosclerosis and MAFLD by inhibiting NOD‐like receptor thermal protein domain associated protein 3 in mice. ⁹⁷ Some herbal extracts have also shown significant therapeutic effects. Hirudin attenuates both hepatic steatosis and cardiac hypertrophy, regulates glucose homeostasis, and enhances glycolysis by activating high‐fat diet‐induced expression of p‐Akt in the liver and cardiac tissues of mice. ⁹⁸ Nutritional drugs containing bergamot and artichoke extracts improve peripheral vascular endothelial function in adults with hepatic steatosis and early atherosclerosis. ⁹⁹

CONCLUSIONS

Metabolic disorders that lead to CVD have received much attention, but fewer studies have explored the relationship between metabolic imbalance and CVD from the perspective of the liver. From the perspective of metabolic homeostasis imbalance, we have thoroughly explored the extensive associations of glucose and lipid metabolism and related inflammation, protein synthesis and metabolism, intestinal microbiota, and genetic factors between MAFLD and MI. A large body of observational data strongly associates MASLD with CVD, and the “double whammy” of concurrent cardiac and hepatic injury accelerates cardiovascular events, but the mechanisms of the heart–hepatic axis have been poorly explored, particularly the lack of attention to direct hepatic–hepatic communication outside of metabolic factors. Notably, interorgan communication has been found to be widespread in a variety of major disease processes such as metabolic diseases and CVD, ¹⁰⁰ the components of the liver–heart axis involve various factors, including secreted proteins, extracellular vesicles, immune cell trafficking, and even the gut microbiota. Elucidating the precise mechanisms of liver‐heart communication will offer novel directions and targets for reducing the incidence of cardiovascular events such as MI, promoting cardiac repair after MI, and prevention strategies. Examples include the IL‐6/STAT3/MR/FGF21 signaling axis, and the roles of miR‐122 and miR‐30a‐3p. Studies integrating multiomics data such as sample genomics, single‐cell genomics, and spatial genomics can comprehensively reveal the liver‐heart biological characteristics in disease states, thereby aiding in the development of novel indicators for assessing CVD associated with MAFLD. Furthermore, establishing a follow‐up cohort of patients with MAFLD with complete clinical phenotypes and biological samples is crucial. Leveraging artificial intelligence and machine learning, conducting multiregion, large‐sample, long‐term real‐world observational studies, and multicenter, large‐sample randomized controlled trials of digital or pharmacological treatments for MAFLD is essential. Establishing a resource‐sharing MAFLD dynamic cohort research big data platform to facilitate early, precise, and stratified prevention and treatment can further clarify effective targets impacting cardiovascular health, providing new directions for the prevention and treatment of CVD and MI.

Sources of Funding

This work was supported by the Xiyuan Hospital's Support Program for Leading Talents in Traditional Chinese Medicine (0202213), Hospital capability enhancement project of Xiyuan Hospital of CACMS (XYZX0201‐10), The Excellent Young Science and Technology Talent Cultivation Special Project of CACMS (CI2023D006) and the Young Qihuang Scholar of the “Tens of millions talent project of China”.

Disclosures

None.

Acknowledgments

Conceptualization: Yue Liu; data curation: Jing Cui, Qian Xu and Mengmeng Zhu; funding acquisition: Yue Liu and Yanfei Liu; project administration: Yue Liu and Yanfei Liu; visualization: Jing Cui and Wenting Wang; roles/writing—original draft: Jing Cui and Wenting Wang; and writing—review and editing: Yue Liu, Yanfei Liu and Yiwen Li.

This article was sent to Marijana Vujkovic, PhD, Assistant Editor, for review by expert referees, editorial decision, and final disposition.

For Sources of Funding and Disclosures, see page 13.

References

1. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, Romero D, Abdelmalek MF, Anstee QM, Arab JP, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023;79:1542–1556. doi: 10.1016/j.jhep.2023.06.003 [DOI] [PubMed] [Google Scholar]
2. Wong RJ, Cheung R. Trends in the prevalence of metabolic dysfunction‐associated fatty liver disease in the United States, 2011–2018. Clin Gastroenterol Hepatol. 2022;20:e610–e613. doi: 10.1016/j.cgh.2021.01.030 [DOI] [PubMed] [Google Scholar]
3. Zhou J, Zhou F, Wang W, Zhang XJ, Ji YX, Zhang P, She ZG, Zhu L, Cai J, Li H. Epidemiological features of NAFLD from 1999 to 2018 in China. Hepatology. 2020;71:1851–1864. doi: 10.1002/hep.31150 [DOI] [PubMed] [Google Scholar]
4. Abosheaishaa H, Hussein M, Ghallab M, Abdelhamid M, Balassiano N, Ahammed MR, Baig MA, Khan J, Elshair M, Soliman MY, et al. Association between non‐alcoholic fatty liver disease and coronary artery disease outcomes: a systematic review and meta‐analysis. Diabetes Metab Syndr. 2024;18:102938. doi: 10.1016/j.dsx.2023.102938 [DOI] [PubMed] [Google Scholar]
5. Loomba R, Friedman SL, Shulman GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell. 2021;184:2537–2564. doi: 10.1016/j.cell.2021.04.015 [DOI] [PMC free article] [PubMed] [Google Scholar]
6. Magkos F, Su X, Bradley D, Fabbrini E, Conte C, Eagon JC, Varela JE, Brunt EM, Patterson BW, Klein S. Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects. Gastroenterology. 2012;142:1444–1446.e1442. doi: 10.1053/j.gastro.2012.03.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
7. Wueest S, Item F, Lucchini FC, Challa TD, Müller W, Blüher M, Konrad D. Mesenteric fat lipolysis mediates obesity‐associated hepatic steatosis and insulin resistance. Diabetes. 2016;65:140–148. doi: 10.2337/db15-0941 [DOI] [PubMed] [Google Scholar]
8. Yu Y, Maguire TG, Alwine JC. ChREBP, a glucose‐responsive transcriptional factor, enhances glucose metabolism to support biosynthesis in human cytomegalovirus‐infected cells. Proc Natl Acad Sci USA. 2014;111:1951–1956. doi: 10.1073/pnas.1310779111 [DOI] [PMC free article] [PubMed] [Google Scholar]
9. Schmitt VH, Hobohm L, Münzel T, Wenzel P, Gori T, Keller K. Impact of diabetes mellitus on mortality rates and outcomes in myocardial infarction. Diabetes Metab. 2021;47:101211. doi: 10.1016/j.diabet.2020.11.003 [DOI] [PubMed] [Google Scholar]
10. Olubamwo OO, Virtanen JK, Voutilainen A, Kauhanen J, Pihlajamäki J, Tuomainen TP. Association of fatty liver index with the risk of incident cardiovascular disease and acute myocardial infarction. Eur J Gastroenterol Hepatol. 2018;30:1047–1054. doi: 10.1097/meg.0000000000001183 [DOI] [PubMed] [Google Scholar]
11. Kim D, Konyn P, Sandhu KK, Dennis BB, Cheung AC, Ahmed A. Metabolic dysfunction‐associated fatty liver disease is associated with increased all‐cause mortality in the United States. J Hepatol. 2021;75:1284–1291. doi: 10.1016/j.jhep.2021.07.035 [DOI] [PubMed] [Google Scholar]
12. Targher G, Tilg H, Byrne CD. Non‐alcoholic fatty liver disease: a multisystem disease requiring a multidisciplinary and holistic approach. Lancet Gastroenterol Hepatol. 2021;6:578–588. doi: 10.1016/s2468-1253(21)00020-0 [DOI] [PubMed] [Google Scholar]
13. Stürzebecher PE, Katzmann JL, Laufs U. What is 'remnant cholesterol'? Eur Heart J. 2023;44:1446–1448. doi: 10.1093/eurheartj/ehac783 [DOI] [PubMed] [Google Scholar]
14. Mahabadi AA, Berg MH, Lehmann N, Kälsch H, Bauer M, Kara K, Dragano N, Moebus S, Jöckel KH, Erbel R, et al. Association of epicardial fat with cardiovascular risk factors and incident myocardial infarction in the general population: the Heinz Nixdorf recall study. J Am Coll Cardiol. 2013;61:1388–1395. doi: 10.1016/j.jacc.2012.11.062 [DOI] [PubMed] [Google Scholar]
15. Verhaegen AA, Van Gaal LF. Drugs affecting body weight, body fat distribution, and metabolic function‐mechanisms and possible therapeutic or preventive measures: an update. Curr Obes Rep. 2021;10:1–13. doi: 10.1007/s13679-020-00419-5 [DOI] [PubMed] [Google Scholar]
16. Armandi A, Rosso C, Caviglia GP, Bugianesi E. Insulin resistance across the spectrum of nonalcoholic fatty liver disease. Metabolites. 2021;11:155. doi: 10.3390/metabo11030155 [DOI] [PMC free article] [PubMed] [Google Scholar]
17. Sun JY, Du LJ, Shi XR, Zhang YY, Liu Y, Wang YL, Chen BY, Liu T, Zhu H, Liu Y, et al. An IL‐6/STAT3/MR/FGF21 axis mediates heart‐liver cross‐talk after myocardial infarction. Sci Adv. 2023;9:eade4110. doi: 10.1126/sciadv.ade4110 [DOI] [PMC free article] [PubMed] [Google Scholar]
18. Jia H, Cheng J, Zhou Q, Peng J, Pan Y, Han H. Fibroblast growth factor 21 attenuates inflammation and oxidative stress in atherosclerotic rat via enhancing the Nrf1‐ARE signaling pathway. Int J Clin Exp Pathol. 2018;11:1308–1317. [PMC free article] [PubMed] [Google Scholar]
19. Zhou B, Xiao M, Hu H, Pei X, Xue Y, Miao G, Wang J, Li W, Du Y, Zhang P, et al. Cardioprotective role of SIRT5 in response to acute ischemia through a novel liver‐cardiac crosstalk mechanism. Front Cell Dev Biol. 2021;9:687559. doi: 10.3389/fcell.2021.687559 [DOI] [PMC free article] [PubMed] [Google Scholar]
20. Li L, Cui L, Lin P, Liu Z, Bao S, Ma X, Nan H, Zhu W, Cen J, Mao Y, et al. Kupffer‐cell‐derived IL‐6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury‐specific enhancers. Cell Stem Cell. 2023;30:283–299.e289. doi: 10.1016/j.stem.2023.01.009 [DOI] [PubMed] [Google Scholar]
21. Li Y, Feng J, Song S, Li H, Yang H, Zhou B, Li Y, Yue Z, Lian H, Liu L, et al. gp130 controls cardiomyocyte proliferation and heart regeneration. Circulation. 2020;142:967–982. doi: 10.1161/circulationaha.119.044484 [DOI] [PubMed] [Google Scholar]
22. Chen X, Chen S, Pang J, Huang R, You Y, Zhang H, Xiao J, Xue H, Ling W. Hepatic steatosis aggravates atherosclerosis via small extracellular vesicle‐mediated inhibition of cellular cholesterol efflux. J Hepatol. 2023;79:1491–1501. doi: 10.1016/j.jhep.2023.08.023 [DOI] [PubMed] [Google Scholar]
23. Schneider KM, Mohs A, Gui W, Galvez EJC, Candels LS, Hoenicke L, Muthukumarasamy U, Holland CH, Elfers C, Kilic K, et al. Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment. Nat Commun. 2022;13:3964. doi: 10.1038/s41467-022-31312-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
24. Kasai Y, Kessoku T, Tanaka K, Yamamoto A, Takahashi K, Kobayashi T, Iwaki M, Ozaki A, Nogami A, Honda Y, et al. Association of serum and fecal bile acid patterns with liver fibrosis in biopsy‐proven nonalcoholic fatty liver disease: an observational study. Clin Transl Gastroenterol. 2022;13:e00503. doi: 10.14309/ctg.0000000000000503 [DOI] [PMC free article] [PubMed] [Google Scholar]
25. Alghamdi W, Mosli M, Alqahtani SA. Gut microbiota in MAFLD: therapeutic and diagnostic implications. Ther Adv Endocrinol Metab. 2024;15:20420188241242937. doi: 10.1177/20420188241242937 [DOI] [PMC free article] [PubMed] [Google Scholar]
26. Mouries J, Brescia P, Silvestri A, Spadoni I, Sorribas M, Wiest R, Mileti E, Galbiati M, Invernizzi P, Adorini L, et al. Microbiota‐driven gut vascular barrier disruption is a prerequisite for non‐alcoholic steatohepatitis development. J Hepatol. 2019;71:1216–1228. doi: 10.1016/j.jhep.2019.08.005 [DOI] [PMC free article] [PubMed] [Google Scholar]
27. Soppert J, Brandt EF, Heussen NM, Barzakova E, Blank LM, Kuepfer L, Hornef MW, Trebicka J, Jankowski J, Berres ML, et al. Blood endotoxin levels as biomarker of nonalcoholic fatty liver disease: a systematic review and meta‐analysis. Clin Gastroenterol Hepatol. 2023;21:2746–2758. doi: 10.1016/j.cgh.2022.11.030 [DOI] [PubMed] [Google Scholar]
28. Mbaye B, Borentain P, Magdy Wasfy R, Alou MT, Armstrong N, Mottola G, Meddeb L, Ranque S, Gérolami R, Million M, et al. Endogenous ethanol and triglyceride production by gut Pichia kudriavzevii, Candida albicans and Candida glabrata yeasts in non‐alcoholic steatohepatitis. Cells. 2022;11:11. doi: 10.3390/cells11213390 [DOI] [PMC free article] [PubMed] [Google Scholar]
29. Raverdy V, Tavaglione F, Chatelain E, Lassailly G, De Vincentis A, Vespasiani‐Gentilucci U, Qadri SF, Caiazzo R, Verkindt H, Saponaro C, et al. Data‐driven cluster analysis identifies distinct types of metabolic dysfunction‐associated steatotic liver disease. Nat Med. 2024;30:3624–3633. doi: 10.1038/s41591-024-03283-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
30. Mouzaki M, Wang AY, Bandsma R, Comelli EM, Arendt BM, Zhang L, Fung S, Fischer SE, McGilvray IG, Allard JP. Bile acids and dysbiosis in non‐alcoholic fatty liver disease. PLoS One. 2016;11:e0151829. doi: 10.1371/journal.pone.0151829 [DOI] [PMC free article] [PubMed] [Google Scholar]
31. Wang SZ, Yu YJ, Adeli K. Role of gut microbiota in neuroendocrine regulation of carbohydrate and lipid metabolism via the microbiota‐gut‐brain‐liver axis. Microorganisms. 2020;8:8. doi: 10.3390/microorganisms8040527 [DOI] [PMC free article] [PubMed] [Google Scholar]
32. He J, Zhang P, Shen L, Niu L, Tan Y, Chen L, Zhao Y, Bai L, Hao X, Li X, et al. Short‐chain fatty acids and their association with Signalling pathways in inflammation, glucose and lipid metabolism. Int J Mol Sci. 2020;21:21. doi: 10.3390/ijms21176356 [DOI] [PMC free article] [PubMed] [Google Scholar]
33. Matsumoto K, Ichimura M, Tsuneyama K, Moritoki Y, Tsunashima H, Omagari K, Hara M, Yasuda I, Miyakawa H, Kikuchi K. Fructo‐oligosaccharides and intestinal barrier function in a methionine‐choline‐deficient mouse model of nonalcoholic steatohepatitis. PLoS One. 2017;12:e0175406. doi: 10.1371/journal.pone.0175406 [DOI] [PMC free article] [PubMed] [Google Scholar]
34. Nemet I, Saha PP, Gupta N, Zhu W, Romano KA, Skye SM, Cajka T, Mohan ML, Li L, Wu Y, et al. A cardiovascular disease‐linked gut microbial metabolite acts via adrenergic receptors. Cell. 2020;180:862–877.e822. doi: 10.1016/j.cell.2020.02.016 [DOI] [PMC free article] [PubMed] [Google Scholar]
35. Hu S, Zhu Y, Zhao X, Li R, Shao G, Gong D, Hu C, Liu H, Xu K, Liu C, et al. Hepatocytic lipocalin‐2 controls HDL metabolism and atherosclerosis via Nedd4‐1‐SR‐BI axis in mice. Dev Cell. 2023;58:2326–2337.e2325. doi: 10.1016/j.devcel.2023.09.007 [DOI] [PubMed] [Google Scholar]
36. Xu Y, Li Y, Jadhav K, Pan X, Zhu Y, Hu S, Chen S, Chen L, Tang Y, Wang HH, et al. Hepatocyte ATF3 protects against atherosclerosis by regulating HDL and bile acid metabolism. Nat Metab. 2021;3:59–74. doi: 10.1038/s42255-020-00331-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
37. van Zwol W, Rimbert A, Wolters JC, Smit M, Bloks VW, Kloosterhuis NJ, Huijkman NCA, Koster MH, Tharehalli U, de Neck SM, et al. Loss of hepatic SMLR1 causes hepatosteatosis and protects against atherosclerosis due to decreased hepatic VLDL secretion. Hepatology. 2023;78:1418–1432. doi: 10.1002/hep.32709 [DOI] [PMC free article] [PubMed] [Google Scholar]
38. Pol CJ, Pollak NM, Jurczak MJ, Zacharia E, Karagiannides I, Kyriazis ID, Ntziachristos P, Scerbo DA, Brown BR, Aifantis I, et al. Cardiac myocyte KLF5 regulates body weight via alteration of cardiac FGF21. Biochim Biophys Acta Mol basis Dis. 2019;1865:2125–2137. doi: 10.1016/j.bbadis.2019.04.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
39. Ji Q, Zhao Y, Yuan A, Pu J, He B. Deficiency of liver‐X‐receptor‐α reduces glucose uptake and worsens post‐myocardial infarction remodeling. Biochem Biophys Res Commun. 2017;488:489–495. doi: 10.1016/j.bbrc.2017.05.072 [DOI] [PubMed] [Google Scholar]
40. Xu Y, Li F, Zalzala M, Xu J, Gonzalez FJ, Adorini L, Lee YK, Yin L, Zhang Y. Farnesoid X receptor activation increases reverse cholesterol transport by modulating bile acid composition and cholesterol absorption in mice. Hepatology. 2016;64:1072–1085. doi: 10.1002/hep.28712 [DOI] [PMC free article] [PubMed] [Google Scholar]
41. Wu Q, Sun L, Hu X, Wang X, Xu F, Chen B, Liang X, Xia J, Wang P, Aibara D, et al. Suppressing the intestinal farnesoid X receptor/sphingomyelin phosphodiesterase 3 axis decreases atherosclerosis. J Clin Invest. 2021;131:131. doi: 10.1172/jci142865 [DOI] [PMC free article] [PubMed] [Google Scholar]
42. Qiang S, Tao L, Zhou J, Wang Q, Wang K, Lu M, Wang W, Han L, Xue S, Chen Y, et al. Knockout of farnesoid X receptor aggravates process of diabetic cardiomyopathy. Diabetes Res Clin Pract. 2020;161:108033. doi: 10.1016/j.diabres.2020.108033 [DOI] [PubMed] [Google Scholar]
43. Yang H, Luo Y, Lai X. The comprehensive role of apoptosis inhibitor of macrophage (AIM) in pathological conditions. Clin Exp Immunol. 2023;212:184–198. doi: 10.1093/cei/uxac095 [DOI] [PMC free article] [PubMed] [Google Scholar]
44. Bárcena C, Aran G, Perea L, Sanjurjo L, Téllez É, Oncins A, Masnou H, Serra I, García‐Gallo M, Kremer L, et al. CD5L is a pleiotropic player in liver fibrosis controlling damage, fibrosis and immune cell content. EBioMedicine. 2019;43:513–524. doi: 10.1016/j.ebiom.2019.04.052 [DOI] [PMC free article] [PubMed] [Google Scholar]
45. Ishikawa S, Noma T, Fu HY, Matsuzaki T, Ishizawa M, Ishikawa K, Murakami K, Nishimoto N, Nishiyama A, Minamino T. Apoptosis inhibitor of macrophage depletion decreased M1 macrophage accumulation and the incidence of cardiac rupture after myocardial infarction in mice. PLoS One. 2017;12:e0187894. doi: 10.1371/journal.pone.0187894 [DOI] [PMC free article] [PubMed] [Google Scholar]
46. Chadani H, Usui S, Inoue O, Kusayama T, Takashima SI, Kato T, Murai H, Furusho H, Nomura A, Misu H, et al. Endogenous Selenoprotein P, a liver‐derived secretory protein, mediates myocardial ischemia/reperfusion injury in mice. Int J Mol Sci. 2018;19:19. doi: 10.3390/ijms19030878 [DOI] [PMC free article] [PubMed] [Google Scholar]
47. Ying T, Wu L, Lan T, Wei Z, Hu D, Ke Y, Jiang Q, Fang J. Adropin inhibits the progression of atherosclerosis in ApoE(−/−)/Enho(−/−) mice by regulating endothelial‐to‐mesenchymal transition. Cell Death Dis. 2023;9:402. doi: 10.1038/s41420-023-01697-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
48. Emoto M, Mori K, Lee E, Kawano N, Yamazaki Y, Tsuchikura S, Morioka T, Koyama H, Shoji T, Inaba M, et al. Fetuin‐a and atherosclerotic calcified plaque in patients with type 2 diabetes mellitus. Metabolism. 2010;59:873–878. doi: 10.1016/j.metabol.2009.10.005 [DOI] [PubMed] [Google Scholar]
49. Jung SH, Lee D, Jin H, Lee HM, Ko HM, Lee KJ, Kim SJ, Ryu Y, Choi WS, Kim B, et al. Fetuin‐B regulates vascular plaque rupture via TGF‐β receptor‐mediated Smad pathway in vascular smooth muscle cells. Pflugers Arch. 2020;472:571–581. doi: 10.1007/s00424-020-02385-2 [DOI] [PubMed] [Google Scholar]
50. Xing W, Tan Y, Li K, Tian P, Tian F, Zhang H. Upregulated hepatokine fetuin B aggravates myocardial ischemia/reperfusion injury through inhibiting insulin signaling in diabetic mice. J Mol Cell Cardiol. 2021;151:163–172. doi: 10.1016/j.yjmcc.2020.03.002 [DOI] [PubMed] [Google Scholar]
51. Mailer RK, Rangaswamy C, Konrath S, Emsley J, Renné T. An update on factor XII‐driven vascular inflammation. Biochim Biophys Acta, Mol Cell Res. 2022;1869:119166. doi: 10.1016/j.bbamcr.2021.119166 [DOI] [PubMed] [Google Scholar]
52. Cao Y, Wang Y, Zhou Z, Pan C, Jiang L, Zhou Z, Meng Y, Charugundla S, Li T, Allayee H, et al. Liver‐heart cross‐talk mediated by coagulation factor XI protects against heart failure. Science. 2022;377:1399–1406. doi: 10.1126/science.abn0910 [DOI] [PMC free article] [PubMed] [Google Scholar]
53. Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J Hepatol. 2018;68:268–279. doi: 10.1016/j.jhep.2017.09.003 [DOI] [PubMed] [Google Scholar]
54. Banini BA, Kumar DP, Cazanave S, Seneshaw M, Mirshahi F, Santhekadur PK, Wang L, Guan HP, Oseini AM, Alonso C, et al. Identification of a metabolic, transcriptomic, and molecular signature of Patatin‐like phospholipase domain containing 3‐mediated acceleration of steatohepatitis. Hepatology. 2021;73:1290–1306. doi: 10.1002/hep.31609 [DOI] [PMC free article] [PubMed] [Google Scholar]
55. Xia M, Ma S, Huang Q, Zeng H, Ge J, Xu W, Wu Q, Wu L, Li X, Ma H, et al. NAFLD‐related gene polymorphisms and all‐cause and cause‐specific mortality in an Asian population: the Shanghai Changfeng study. Aliment Pharmacol Ther. 2022;55:705–721. doi: 10.1111/apt.16772 [DOI] [PubMed] [Google Scholar]
56. Lauridsen BK, Stender S, Kristensen TS, Kofoed KF, Køber L, Nordestgaard BG, Tybjærg‐Hansen A. Liver fat content, non‐alcoholic fatty liver disease, and ischaemic heart disease: mendelian randomization and meta‐analysis of 279 013 individuals. Eur Heart J. 2018;39:385–393. doi: 10.1093/eurheartj/ehx662 [DOI] [PubMed] [Google Scholar]
57. Simons N, Isaacs A, Koek GH, Kuč S, Schaper NC, Brouwers M. PNPLA3, TM6SF2, and MBOAT7 genotypes and coronary artery disease. Gastroenterology. 2017;152:912–913. doi: 10.1053/j.gastro.2016.12.020 [DOI] [PubMed] [Google Scholar]
58. Luukkonen PK, Qadri S, Lehtimäki TE, Juuti A, Sammalkorpi H, Penttilä AK, Hakkarainen A, Orho‐Melander M, Arola J, Yki‐Järvinen H. The PNPLA3‐I148M variant confers an antiatherogenic lipid profile in insulin‐resistant patients. J Clin Endocrinol Metab. 2021;106:e300–e315. doi: 10.1210/clinem/dgaa729 [DOI] [PubMed] [Google Scholar]
59. Pelusi S, Baselli G, Pietrelli A, Dongiovanni P, Donati B, McCain MV, Meroni M, Fracanzani AL, Romagnoli R, Petta S, et al. Rare pathogenic variants predispose to hepatocellular carcinoma in nonalcoholic fatty liver disease. Sci Rep. 2019;9:3682. doi: 10.1038/s41598-019-39998-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
60. Jamialahmadi O, De Vincentis A, Tavaglione F, Malvestiti F, Li‐Gao R, Mancina RM, Alvarez M, Gelev K, Maurotti S, Vespasiani‐Gentilucci U, et al. Partitioned polygenic risk scores identify distinct types of metabolic dysfunction‐associated steatotic liver disease. Nat Med. 2024;30:3614–3623. doi: 10.1038/s41591-024-03284-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
61. Chow JD, Jones ME, Prelle K, Simpson ER, Boon WC. A selective estrogen receptor α agonist ameliorates hepatic steatosis in the male aromatase knockout mouse. J Endocrinol. 2011;210:323–334. doi: 10.1530/joe-10-0462 [DOI] [PubMed] [Google Scholar]
62. Cherubini A, Ostadreza M, Jamialahmadi O, Pelusi S, Rrapaj E, Casirati E, Passignani G, Norouziesfahani M, Sinopoli E, Baselli G, et al. Interaction between estrogen receptor‐α and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women. Nat Med. 2023;29:2643–2655. doi: 10.1038/s41591-023-02553-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
63. Jia Y, Yee JK, Wang C, Nikolaenko L, Diaz‐Arjonilla M, Cohen JN, French SW, Liu PY, Lue Y, Lee WP, et al. Testosterone protects high‐fat/low‐carbohydrate diet‐induced nonalcoholic fatty liver disease in castrated male rats mainly via modulating endoplasmic reticulum stress. Am J Physiol‐Endocrinol Metab. 2018;314:E366–e376. doi: 10.1152/ajpendo.00124.2017 [DOI] [PMC free article] [PubMed] [Google Scholar]
64. Nash E, Nicoll A, Batt N, George J, Perananthan V, Prince D, Wallace M, Gow P, Vaz K, Chitturi S, et al. Drug‐induced liver injury from selective androgen receptor modulators, anabolic‐androgenic steroids and bodybuilding supplements in Australia. Aliment Pharmacol Ther. 2024;59:953–961. doi: 10.1111/apt.17906 [DOI] [PubMed] [Google Scholar]
65. Navarro G, Allard C, Morford JJ, Xu W, Liu S, Molinas AJ, Butcher SM, Fine NH, Blandino‐Rosano M, Sure VN, et al. Androgen excess in pancreatic β cells and neurons predisposes female mice to type 2 diabetes. JCI Insight. 2018;3:e98607. doi: 10.1172/jci.insight.98607 [DOI] [PMC free article] [PubMed] [Google Scholar]
66. Rinella ME, Neuschwander‐Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S, Barb D, Kleiner DE, Loomba R. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77:1797–1835. doi: 10.1097/hep.0000000000000323 [DOI] [PMC free article] [PubMed] [Google Scholar]
67. Wu H. European association for the study of the liver (EASL) congress 2024. Lancet Reg Health Eur. 2024;43:100980. doi: 10.1016/j.lanepe.2024.100980 [DOI] [PMC free article] [PubMed] [Google Scholar]
68. Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R, Labriola D, Moussa SE, Neff GW, Rinella ME, et al. A phase 3, randomized, controlled trial of Resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390:497–509. doi: 10.1056/NEJMoa2309000 [DOI] [PubMed] [Google Scholar]
69. Hamasaki M, Sakane N, Kotani K. Nonalcoholic fatty liver disease risk and proprotein convertase subtilisin Kexin 9 in familial hypercholesterolemia under statin treatment. Nutrients. 2024;16:3686. doi: 10.3390/nu16213686 [DOI] [PMC free article] [PubMed] [Google Scholar]
70. Dai W, Xu B, Li P, Weng J. Statins for the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: a systematic review and meta‐analysis. Am J Ther. 2023;30:e17–e25. doi: 10.1097/mjt.0000000000001499 [DOI] [PubMed] [Google Scholar]
71. Zou B, Odden MC, Nguyen MH. Statin use and reduced hepatocellular carcinoma risk in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2023;21:435–444.e436. doi: 10.1016/j.cgh.2022.01.057 [DOI] [PubMed] [Google Scholar]
72. Yoo J, Jeon J, Baik M, Kim J. Effect of statins for primary prevention of cardiovascular disease according to the fatty liver index. J Epidemiol Glob Health. 2024;14:710–719. doi: 10.1007/s44197-024-00205-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
73. Zhang S, Ren X, Zhang B, Lan T, Liu B. A systematic review of statins for the treatment of nonalcoholic steatohepatitis: safety, efficacy, and mechanism of action. Molecules. 2024;29:1859. doi: 10.3390/molecules29081859 [DOI] [PMC free article] [PubMed] [Google Scholar]
74. Khan SU, Yedlapati SH, Lone AN, Hao Q, Guyatt G, Delvaux N, Bekkering GET, Vandvik PO, Riaz IB, Li S, et al. PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta‐analysis. BMJ. 2022;377:e069116. doi: 10.1136/bmj-2021-069116 [DOI] [PubMed] [Google Scholar]
75. Castellano‐Castillo D, Núñez‐Sánchez M, Balaguer‐Román A, Martínez‐Sánchez MA, Fernández‐Ruiz VE, Ferrer‐Gómez M, Martínez CM, Frutos MD, Queipo‐Ortuño MI, Cardona F, et al. The role of PCSK9 in metabolic dysfunction‐associated steatotic liver disease and its impact on bariatric surgery outcomes. Surg Obes Relat Dis. 2024;20:652–659. doi: 10.1016/j.soard.2024.01.017 [DOI] [PubMed] [Google Scholar]
76. Lee S, Zhang C, Liu Z, Klevstig M, Mukhopadhyay B, Bergentall M, Cinar R, Ståhlman M, Sikanic N, Park JK, et al. Network analyses identify liver‐specific targets for treating liver diseases. Mol Syst Biol. 2017;13:938. doi: 10.15252/msb.20177703 [DOI] [PMC free article] [PubMed] [Google Scholar]
77. Lebeau PF, Byun JH, Platko K, Al‐Hashimi AA, Lhoták Š, MacDonald ME, Mejia‐Benitez A, Prat A, Igdoura SA, Trigatti B, et al. Pcsk9 knockout exacerbates diet‐induced non‐alcoholic steatohepatitis, fibrosis and liver injury in mice. JHEP Rep. 2019;1:418–429. doi: 10.1016/j.jhepr.2019.10.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
78. Sachan V, Susan‐Resiga D, Lam K, Seidah NG. The biology and clinical implications of PCSK7. Endocr Rev. 2025;46:281–299. doi: 10.1210/endrev/bnae031 [DOI] [PMC free article] [PubMed] [Google Scholar]
79. Krishnan A, Schneider CV, Hadi Y, Mukherjee D, AlShehri B, Alqahtani SA. Cardiovascular and mortality outcomes with GLP‐1 receptor agonists vs other glucose‐lowering drugs in individuals with NAFLD and type 2 diabetes: a large population‐based matched cohort study. Diabetologia. 2024;67:483–493. doi: 10.1007/s00125-023-06057-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
80. Morieri ML, Targher G, Lapolla A, D'Ambrosio M, Tadiotto F, Rigato M, Frison V, Paccagnella A, Simioni N, Avogaro A, et al. Changes in markers of hepatic steatosis and fibrosis in patients with type 2 diabetes during treatment with glucagon‐like peptide‐1 receptor agonists. A multicenter retrospective longitudinal study. Nutr Metab Cardiovasc Dis. 2021;31:3474–3483. doi: 10.1016/j.numecd.2021.08.049 [DOI] [PubMed] [Google Scholar]
81. Mantovani A, Petracca G, Beatrice G, Csermely A, Lonardo A, Targher G. Glucagon‐like Peptide‐1 receptor agonists for treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: an updated meta‐analysis of randomized controlled trials. Metabolites. 2021;11:73. doi: 10.3390/metabo11020073 [DOI] [PMC free article] [PubMed] [Google Scholar]
82. Marso SP, Daniels GH, Brown‐Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–322. doi: 10.1056/NEJMoa1603827 [DOI] [PMC free article] [PubMed] [Google Scholar]
83. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, Probstfield J, Riesmeyer JS, Riddle MC, Rydén L, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double‐blind, randomised placebo‐controlled trial. Lancet. 2019;394:121–130. doi: 10.1016/s0140-6736(19)31149-3 [DOI] [PubMed] [Google Scholar]
84. Green JB, Hernandez AF, D'Agostino RB, Granger CB, Janmohamed S, Jones NP, Leiter LA, Noronha D, Russell R, Sigmon K, et al. Harmony outcomes: a randomized, double‐blind, placebo‐controlled trial of the effect of albiglutide on major cardiovascular events in patients with type 2 diabetes mellitus‐rationale, design, and baseline characteristics. Am Heart J. 2018;203:30–38. doi: 10.1016/j.ahj.2018.03.030 [DOI] [PubMed] [Google Scholar]
85. Seghieri M, Christensen AS, Andersen A, Solini A, Knop FK, Vilsbøll T. Future perspectives on GLP‐1 receptor agonists and GLP‐1/glucagon receptor Co‐agonists in the treatment of NAFLD. Front Endocrinol. 2018;9:649. doi: 10.3389/fendo.2018.00649 [DOI] [PMC free article] [PubMed] [Google Scholar]
86. Yu X, Hao M, Liu Y, Ma X, Lin W, Xu Q, Zhou H, Shao N, Kuang H. Liraglutide ameliorates non‐alcoholic steatohepatitis by inhibiting NLRP3 inflammasome and pyroptosis activation via mitophagy. Eur J Pharmacol. 2019;864:172715. doi: 10.1016/j.ejphar.2019.172715 [DOI] [PubMed] [Google Scholar]
87. Alam S, Ghosh J, Mustafa G, Kamal M, Ahmad N. Effect of sitagliptin on hepatic histological activity and fibrosis of nonalcoholic steatohepatitis patients: a 1‐year randomized control trial. Hepatol Med Policy. 2018;10:23–31. doi: 10.2147/hmer.S158053 [DOI] [PMC free article] [PubMed] [Google Scholar]
88. Wang X, Hausding M, Weng SY, Kim YO, Steven S, Klein T, Daiber A, Schuppan D. Gliptins suppress inflammatory macrophage activation to mitigate inflammation, fibrosis, oxidative stress, and vascular dysfunction in models of nonalcoholic steatohepatitis and liver fibrosis. Antioxid Redox Signal. 2018;28:87–109. doi: 10.1089/ars.2016.6953 [DOI] [PubMed] [Google Scholar]
89. Yan J, Yao B, Kuang H, Yang X, Huang Q, Hong T, Li Y, Dou J, Yang W, Qin G, et al. Liraglutide, sitagliptin, and insulin glargine added to metformin: the effect on body weight and intrahepatic lipid in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Hepatology. 2019;69:2414–2426. doi: 10.1002/hep.30320 [DOI] [PMC free article] [PubMed] [Google Scholar]
90. Panico C, Bonora B, Camera A, Chilelli NC, Prato GD, Favacchio G, Grancini V, Resi V, Rondinelli M, Zarra E, et al. Pathophysiological basis of the cardiological benefits of SGLT‐2 inhibitors: a narrative review. Cardiovasc Diabetol. 2023;22:164. doi: 10.1186/s12933-023-01855-y [DOI] [PMC free article] [PubMed] [Google Scholar]
91. Nasiri‐Ansari N, Nikolopoulou C, Papoutsi K, Kyrou I, Mantzoros CS, Kyriakopoulos G, Chatzigeorgiou A, Kalotychou V, Randeva MS, Chatha K, et al. Empagliflozin attenuates non‐alcoholic fatty liver disease (NAFLD) in high fat diet fed ApoE((−/−)) mice by activating autophagy and reducing ER stress and apoptosis. Int J Mol Sci. 2021;22:818. doi: 10.3390/ijms22020818 [DOI] [PMC free article] [PubMed] [Google Scholar]
92. Lee TM, Chang NC, Lin SZ. Dapagliflozin, a selective SGLT2 inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic Biol Med. 2017;104:298–310. doi: 10.1016/j.freeradbiomed.2017.01.035 [DOI] [PubMed] [Google Scholar]
93. Schoeler M, Caesar R. Dietary lipids, gut microbiota and lipid metabolism. Rev Endocr Metab Disord. 2019;20:461–472. doi: 10.1007/s11154-019-09512-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
94. Fu Y, Wang Y, Gao H, Li D, Jiang R, Ge L, Tong C, Xu K. Associations among dietary Omega‐3 polyunsaturated fatty acids, the gut microbiota, and intestinal immunity. Mediat Inflamm. 2021;2021:8879227–8879211. doi: 10.1155/2021/8879227 [DOI] [PMC free article] [PubMed] [Google Scholar]
95. Aron‐Wisnewsky J, Warmbrunn MV, Nieuwdorp M, Clément K. Nonalcoholic fatty liver disease: modulating gut microbiota to improve severity? Gastroenterology. 2020;158:1881–1898. doi: 10.1053/j.gastro.2020.01.049 [DOI] [PubMed] [Google Scholar]
96. du Preez R, Wanyonyi S, Mouatt P, Panchal SK, Brown L. Saskatoon berry Amelanchier alnifolia regulates glucose metabolism and improves cardiovascular and liver signs of diet‐induced metabolic syndrome in rats. Nutrients. 2020;12:931. doi: 10.3390/nu12040931 [DOI] [PMC free article] [PubMed] [Google Scholar]
97. Lu Z, Liu L, Zhao S, Zhao J, Li S, Li M. Apigenin attenuates atherosclerosis and non‐alcoholic fatty liver disease through inhibition of NLRP3 inflammasome in mice. Sci Rep. 2023;13:7996. doi: 10.1038/s41598-023-34654-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
98. Hu W, Li M, Sun W, Li Q, Xi H, Qiu Y, Wang R, Ding Q, Wang Z, Yu Y, et al. Hirsutine ameliorates hepatic and cardiac insulin resistance in high‐fat diet‐induced diabetic mice and in vitro models. Pharmacol Res. 2022;177:105917. doi: 10.1016/j.phrs.2021.105917 [DOI] [PubMed] [Google Scholar]
99. Maurotti S, Pujia R, Ferro Y, Mare R, Russo R, Coppola A, Gazzaruso C, Montalcini T, Pujia A, Paone S, et al. A nutraceutical with Citrus bergamia and Cynara cardunculus improves endothelial function in adults with non‐alcoholic fatty liver disease. Nutrition. 2024;118:112294. doi: 10.1016/j.nut.2023.112294 [DOI] [PubMed] [Google Scholar]
100. Hu S, Hu Y, Yan W. Extracellular vesicle‐mediated interorgan communication in metabolic diseases. Trends Endocrinol Metab. 2023;34:571–582. doi: 10.1016/j.tem.2023.06.002 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0001] 1. Rinella ME, Lazarus JV, Ratziu V, Francque SM, Sanyal AJ, Kanwal F, Romero D, Abdelmalek MF, Anstee QM, Arab JP, et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023;79:1542–1556. doi: 10.1016/j.jhep.2023.06.003 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0002] 2. Wong RJ, Cheung R. Trends in the prevalence of metabolic dysfunction‐associated fatty liver disease in the United States, 2011–2018. Clin Gastroenterol Hepatol. 2022;20:e610–e613. doi: 10.1016/j.cgh.2021.01.030 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0003] 3. Zhou J, Zhou F, Wang W, Zhang XJ, Ji YX, Zhang P, She ZG, Zhu L, Cai J, Li H. Epidemiological features of NAFLD from 1999 to 2018 in China. Hepatology. 2020;71:1851–1864. doi: 10.1002/hep.31150 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0004] 4. Abosheaishaa H, Hussein M, Ghallab M, Abdelhamid M, Balassiano N, Ahammed MR, Baig MA, Khan J, Elshair M, Soliman MY, et al. Association between non‐alcoholic fatty liver disease and coronary artery disease outcomes: a systematic review and meta‐analysis. Diabetes Metab Syndr. 2024;18:102938. doi: 10.1016/j.dsx.2023.102938 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0005] 5. Loomba R, Friedman SL, Shulman GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell. 2021;184:2537–2564. doi: 10.1016/j.cell.2021.04.015 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0006] 6. Magkos F, Su X, Bradley D, Fabbrini E, Conte C, Eagon JC, Varela JE, Brunt EM, Patterson BW, Klein S. Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects. Gastroenterology. 2012;142:1444–1446.e1442. doi: 10.1053/j.gastro.2012.03.003 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0007] 7. Wueest S, Item F, Lucchini FC, Challa TD, Müller W, Blüher M, Konrad D. Mesenteric fat lipolysis mediates obesity‐associated hepatic steatosis and insulin resistance. Diabetes. 2016;65:140–148. doi: 10.2337/db15-0941 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0008] 8. Yu Y, Maguire TG, Alwine JC. ChREBP, a glucose‐responsive transcriptional factor, enhances glucose metabolism to support biosynthesis in human cytomegalovirus‐infected cells. Proc Natl Acad Sci USA. 2014;111:1951–1956. doi: 10.1073/pnas.1310779111 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0009] 9. Schmitt VH, Hobohm L, Münzel T, Wenzel P, Gori T, Keller K. Impact of diabetes mellitus on mortality rates and outcomes in myocardial infarction. Diabetes Metab. 2021;47:101211. doi: 10.1016/j.diabet.2020.11.003 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0010] 10. Olubamwo OO, Virtanen JK, Voutilainen A, Kauhanen J, Pihlajamäki J, Tuomainen TP. Association of fatty liver index with the risk of incident cardiovascular disease and acute myocardial infarction. Eur J Gastroenterol Hepatol. 2018;30:1047–1054. doi: 10.1097/meg.0000000000001183 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0011] 11. Kim D, Konyn P, Sandhu KK, Dennis BB, Cheung AC, Ahmed A. Metabolic dysfunction‐associated fatty liver disease is associated with increased all‐cause mortality in the United States. J Hepatol. 2021;75:1284–1291. doi: 10.1016/j.jhep.2021.07.035 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0012] 12. Targher G, Tilg H, Byrne CD. Non‐alcoholic fatty liver disease: a multisystem disease requiring a multidisciplinary and holistic approach. Lancet Gastroenterol Hepatol. 2021;6:578–588. doi: 10.1016/s2468-1253(21)00020-0 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0013] 13. Stürzebecher PE, Katzmann JL, Laufs U. What is 'remnant cholesterol'? Eur Heart J. 2023;44:1446–1448. doi: 10.1093/eurheartj/ehac783 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0014] 14. Mahabadi AA, Berg MH, Lehmann N, Kälsch H, Bauer M, Kara K, Dragano N, Moebus S, Jöckel KH, Erbel R, et al. Association of epicardial fat with cardiovascular risk factors and incident myocardial infarction in the general population: the Heinz Nixdorf recall study. J Am Coll Cardiol. 2013;61:1388–1395. doi: 10.1016/j.jacc.2012.11.062 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0015] 15. Verhaegen AA, Van Gaal LF. Drugs affecting body weight, body fat distribution, and metabolic function‐mechanisms and possible therapeutic or preventive measures: an update. Curr Obes Rep. 2021;10:1–13. doi: 10.1007/s13679-020-00419-5 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0016] 16. Armandi A, Rosso C, Caviglia GP, Bugianesi E. Insulin resistance across the spectrum of nonalcoholic fatty liver disease. Metabolites. 2021;11:155. doi: 10.3390/metabo11030155 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0017] 17. Sun JY, Du LJ, Shi XR, Zhang YY, Liu Y, Wang YL, Chen BY, Liu T, Zhu H, Liu Y, et al. An IL‐6/STAT3/MR/FGF21 axis mediates heart‐liver cross‐talk after myocardial infarction. Sci Adv. 2023;9:eade4110. doi: 10.1126/sciadv.ade4110 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0018] 18. Jia H, Cheng J, Zhou Q, Peng J, Pan Y, Han H. Fibroblast growth factor 21 attenuates inflammation and oxidative stress in atherosclerotic rat via enhancing the Nrf1‐ARE signaling pathway. Int J Clin Exp Pathol. 2018;11:1308–1317. [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0019] 19. Zhou B, Xiao M, Hu H, Pei X, Xue Y, Miao G, Wang J, Li W, Du Y, Zhang P, et al. Cardioprotective role of SIRT5 in response to acute ischemia through a novel liver‐cardiac crosstalk mechanism. Front Cell Dev Biol. 2021;9:687559. doi: 10.3389/fcell.2021.687559 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0020] 20. Li L, Cui L, Lin P, Liu Z, Bao S, Ma X, Nan H, Zhu W, Cen J, Mao Y, et al. Kupffer‐cell‐derived IL‐6 is repurposed for hepatocyte dedifferentiation via activating progenitor genes from injury‐specific enhancers. Cell Stem Cell. 2023;30:283–299.e289. doi: 10.1016/j.stem.2023.01.009 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0021] 21. Li Y, Feng J, Song S, Li H, Yang H, Zhou B, Li Y, Yue Z, Lian H, Liu L, et al. gp130 controls cardiomyocyte proliferation and heart regeneration. Circulation. 2020;142:967–982. doi: 10.1161/circulationaha.119.044484 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0022] 22. Chen X, Chen S, Pang J, Huang R, You Y, Zhang H, Xiao J, Xue H, Ling W. Hepatic steatosis aggravates atherosclerosis via small extracellular vesicle‐mediated inhibition of cellular cholesterol efflux. J Hepatol. 2023;79:1491–1501. doi: 10.1016/j.jhep.2023.08.023 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0023] 23. Schneider KM, Mohs A, Gui W, Galvez EJC, Candels LS, Hoenicke L, Muthukumarasamy U, Holland CH, Elfers C, Kilic K, et al. Imbalanced gut microbiota fuels hepatocellular carcinoma development by shaping the hepatic inflammatory microenvironment. Nat Commun. 2022;13:3964. doi: 10.1038/s41467-022-31312-5 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0024] 24. Kasai Y, Kessoku T, Tanaka K, Yamamoto A, Takahashi K, Kobayashi T, Iwaki M, Ozaki A, Nogami A, Honda Y, et al. Association of serum and fecal bile acid patterns with liver fibrosis in biopsy‐proven nonalcoholic fatty liver disease: an observational study. Clin Transl Gastroenterol. 2022;13:e00503. doi: 10.14309/ctg.0000000000000503 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0025] 25. Alghamdi W, Mosli M, Alqahtani SA. Gut microbiota in MAFLD: therapeutic and diagnostic implications. Ther Adv Endocrinol Metab. 2024;15:20420188241242937. doi: 10.1177/20420188241242937 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0026] 26. Mouries J, Brescia P, Silvestri A, Spadoni I, Sorribas M, Wiest R, Mileti E, Galbiati M, Invernizzi P, Adorini L, et al. Microbiota‐driven gut vascular barrier disruption is a prerequisite for non‐alcoholic steatohepatitis development. J Hepatol. 2019;71:1216–1228. doi: 10.1016/j.jhep.2019.08.005 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0027] 27. Soppert J, Brandt EF, Heussen NM, Barzakova E, Blank LM, Kuepfer L, Hornef MW, Trebicka J, Jankowski J, Berres ML, et al. Blood endotoxin levels as biomarker of nonalcoholic fatty liver disease: a systematic review and meta‐analysis. Clin Gastroenterol Hepatol. 2023;21:2746–2758. doi: 10.1016/j.cgh.2022.11.030 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0028] 28. Mbaye B, Borentain P, Magdy Wasfy R, Alou MT, Armstrong N, Mottola G, Meddeb L, Ranque S, Gérolami R, Million M, et al. Endogenous ethanol and triglyceride production by gut Pichia kudriavzevii, Candida albicans and Candida glabrata yeasts in non‐alcoholic steatohepatitis. Cells. 2022;11:11. doi: 10.3390/cells11213390 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0029] 29. Raverdy V, Tavaglione F, Chatelain E, Lassailly G, De Vincentis A, Vespasiani‐Gentilucci U, Qadri SF, Caiazzo R, Verkindt H, Saponaro C, et al. Data‐driven cluster analysis identifies distinct types of metabolic dysfunction‐associated steatotic liver disease. Nat Med. 2024;30:3624–3633. doi: 10.1038/s41591-024-03283-1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0030] 30. Mouzaki M, Wang AY, Bandsma R, Comelli EM, Arendt BM, Zhang L, Fung S, Fischer SE, McGilvray IG, Allard JP. Bile acids and dysbiosis in non‐alcoholic fatty liver disease. PLoS One. 2016;11:e0151829. doi: 10.1371/journal.pone.0151829 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0031] 31. Wang SZ, Yu YJ, Adeli K. Role of gut microbiota in neuroendocrine regulation of carbohydrate and lipid metabolism via the microbiota‐gut‐brain‐liver axis. Microorganisms. 2020;8:8. doi: 10.3390/microorganisms8040527 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0032] 32. He J, Zhang P, Shen L, Niu L, Tan Y, Chen L, Zhao Y, Bai L, Hao X, Li X, et al. Short‐chain fatty acids and their association with Signalling pathways in inflammation, glucose and lipid metabolism. Int J Mol Sci. 2020;21:21. doi: 10.3390/ijms21176356 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0033] 33. Matsumoto K, Ichimura M, Tsuneyama K, Moritoki Y, Tsunashima H, Omagari K, Hara M, Yasuda I, Miyakawa H, Kikuchi K. Fructo‐oligosaccharides and intestinal barrier function in a methionine‐choline‐deficient mouse model of nonalcoholic steatohepatitis. PLoS One. 2017;12:e0175406. doi: 10.1371/journal.pone.0175406 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0034] 34. Nemet I, Saha PP, Gupta N, Zhu W, Romano KA, Skye SM, Cajka T, Mohan ML, Li L, Wu Y, et al. A cardiovascular disease‐linked gut microbial metabolite acts via adrenergic receptors. Cell. 2020;180:862–877.e822. doi: 10.1016/j.cell.2020.02.016 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0035] 35. Hu S, Zhu Y, Zhao X, Li R, Shao G, Gong D, Hu C, Liu H, Xu K, Liu C, et al. Hepatocytic lipocalin‐2 controls HDL metabolism and atherosclerosis via Nedd4‐1‐SR‐BI axis in mice. Dev Cell. 2023;58:2326–2337.e2325. doi: 10.1016/j.devcel.2023.09.007 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0036] 36. Xu Y, Li Y, Jadhav K, Pan X, Zhu Y, Hu S, Chen S, Chen L, Tang Y, Wang HH, et al. Hepatocyte ATF3 protects against atherosclerosis by regulating HDL and bile acid metabolism. Nat Metab. 2021;3:59–74. doi: 10.1038/s42255-020-00331-1 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0037] 37. van Zwol W, Rimbert A, Wolters JC, Smit M, Bloks VW, Kloosterhuis NJ, Huijkman NCA, Koster MH, Tharehalli U, de Neck SM, et al. Loss of hepatic SMLR1 causes hepatosteatosis and protects against atherosclerosis due to decreased hepatic VLDL secretion. Hepatology. 2023;78:1418–1432. doi: 10.1002/hep.32709 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0038] 38. Pol CJ, Pollak NM, Jurczak MJ, Zacharia E, Karagiannides I, Kyriazis ID, Ntziachristos P, Scerbo DA, Brown BR, Aifantis I, et al. Cardiac myocyte KLF5 regulates body weight via alteration of cardiac FGF21. Biochim Biophys Acta Mol basis Dis. 2019;1865:2125–2137. doi: 10.1016/j.bbadis.2019.04.010 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0039] 39. Ji Q, Zhao Y, Yuan A, Pu J, He B. Deficiency of liver‐X‐receptor‐α reduces glucose uptake and worsens post‐myocardial infarction remodeling. Biochem Biophys Res Commun. 2017;488:489–495. doi: 10.1016/j.bbrc.2017.05.072 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0040] 40. Xu Y, Li F, Zalzala M, Xu J, Gonzalez FJ, Adorini L, Lee YK, Yin L, Zhang Y. Farnesoid X receptor activation increases reverse cholesterol transport by modulating bile acid composition and cholesterol absorption in mice. Hepatology. 2016;64:1072–1085. doi: 10.1002/hep.28712 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0041] 41. Wu Q, Sun L, Hu X, Wang X, Xu F, Chen B, Liang X, Xia J, Wang P, Aibara D, et al. Suppressing the intestinal farnesoid X receptor/sphingomyelin phosphodiesterase 3 axis decreases atherosclerosis. J Clin Invest. 2021;131:131. doi: 10.1172/jci142865 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0042] 42. Qiang S, Tao L, Zhou J, Wang Q, Wang K, Lu M, Wang W, Han L, Xue S, Chen Y, et al. Knockout of farnesoid X receptor aggravates process of diabetic cardiomyopathy. Diabetes Res Clin Pract. 2020;161:108033. doi: 10.1016/j.diabres.2020.108033 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0043] 43. Yang H, Luo Y, Lai X. The comprehensive role of apoptosis inhibitor of macrophage (AIM) in pathological conditions. Clin Exp Immunol. 2023;212:184–198. doi: 10.1093/cei/uxac095 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0044] 44. Bárcena C, Aran G, Perea L, Sanjurjo L, Téllez É, Oncins A, Masnou H, Serra I, García‐Gallo M, Kremer L, et al. CD5L is a pleiotropic player in liver fibrosis controlling damage, fibrosis and immune cell content. EBioMedicine. 2019;43:513–524. doi: 10.1016/j.ebiom.2019.04.052 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0045] 45. Ishikawa S, Noma T, Fu HY, Matsuzaki T, Ishizawa M, Ishikawa K, Murakami K, Nishimoto N, Nishiyama A, Minamino T. Apoptosis inhibitor of macrophage depletion decreased M1 macrophage accumulation and the incidence of cardiac rupture after myocardial infarction in mice. PLoS One. 2017;12:e0187894. doi: 10.1371/journal.pone.0187894 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0046] 46. Chadani H, Usui S, Inoue O, Kusayama T, Takashima SI, Kato T, Murai H, Furusho H, Nomura A, Misu H, et al. Endogenous Selenoprotein P, a liver‐derived secretory protein, mediates myocardial ischemia/reperfusion injury in mice. Int J Mol Sci. 2018;19:19. doi: 10.3390/ijms19030878 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0047] 47. Ying T, Wu L, Lan T, Wei Z, Hu D, Ke Y, Jiang Q, Fang J. Adropin inhibits the progression of atherosclerosis in ApoE(−/−)/Enho(−/−) mice by regulating endothelial‐to‐mesenchymal transition. Cell Death Dis. 2023;9:402. doi: 10.1038/s41420-023-01697-3 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0048] 48. Emoto M, Mori K, Lee E, Kawano N, Yamazaki Y, Tsuchikura S, Morioka T, Koyama H, Shoji T, Inaba M, et al. Fetuin‐a and atherosclerotic calcified plaque in patients with type 2 diabetes mellitus. Metabolism. 2010;59:873–878. doi: 10.1016/j.metabol.2009.10.005 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0049] 49. Jung SH, Lee D, Jin H, Lee HM, Ko HM, Lee KJ, Kim SJ, Ryu Y, Choi WS, Kim B, et al. Fetuin‐B regulates vascular plaque rupture via TGF‐β receptor‐mediated Smad pathway in vascular smooth muscle cells. Pflugers Arch. 2020;472:571–581. doi: 10.1007/s00424-020-02385-2 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0050] 50. Xing W, Tan Y, Li K, Tian P, Tian F, Zhang H. Upregulated hepatokine fetuin B aggravates myocardial ischemia/reperfusion injury through inhibiting insulin signaling in diabetic mice. J Mol Cell Cardiol. 2021;151:163–172. doi: 10.1016/j.yjmcc.2020.03.002 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0051] 51. Mailer RK, Rangaswamy C, Konrath S, Emsley J, Renné T. An update on factor XII‐driven vascular inflammation. Biochim Biophys Acta, Mol Cell Res. 2022;1869:119166. doi: 10.1016/j.bbamcr.2021.119166 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0052] 52. Cao Y, Wang Y, Zhou Z, Pan C, Jiang L, Zhou Z, Meng Y, Charugundla S, Li T, Allayee H, et al. Liver‐heart cross‐talk mediated by coagulation factor XI protects against heart failure. Science. 2022;377:1399–1406. doi: 10.1126/science.abn0910 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0053] 53. Eslam M, Valenti L, Romeo S. Genetics and epigenetics of NAFLD and NASH: clinical impact. J Hepatol. 2018;68:268–279. doi: 10.1016/j.jhep.2017.09.003 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0054] 54. Banini BA, Kumar DP, Cazanave S, Seneshaw M, Mirshahi F, Santhekadur PK, Wang L, Guan HP, Oseini AM, Alonso C, et al. Identification of a metabolic, transcriptomic, and molecular signature of Patatin‐like phospholipase domain containing 3‐mediated acceleration of steatohepatitis. Hepatology. 2021;73:1290–1306. doi: 10.1002/hep.31609 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0055] 55. Xia M, Ma S, Huang Q, Zeng H, Ge J, Xu W, Wu Q, Wu L, Li X, Ma H, et al. NAFLD‐related gene polymorphisms and all‐cause and cause‐specific mortality in an Asian population: the Shanghai Changfeng study. Aliment Pharmacol Ther. 2022;55:705–721. doi: 10.1111/apt.16772 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0056] 56. Lauridsen BK, Stender S, Kristensen TS, Kofoed KF, Køber L, Nordestgaard BG, Tybjærg‐Hansen A. Liver fat content, non‐alcoholic fatty liver disease, and ischaemic heart disease: mendelian randomization and meta‐analysis of 279 013 individuals. Eur Heart J. 2018;39:385–393. doi: 10.1093/eurheartj/ehx662 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0057] 57. Simons N, Isaacs A, Koek GH, Kuč S, Schaper NC, Brouwers M. PNPLA3, TM6SF2, and MBOAT7 genotypes and coronary artery disease. Gastroenterology. 2017;152:912–913. doi: 10.1053/j.gastro.2016.12.020 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0058] 58. Luukkonen PK, Qadri S, Lehtimäki TE, Juuti A, Sammalkorpi H, Penttilä AK, Hakkarainen A, Orho‐Melander M, Arola J, Yki‐Järvinen H. The PNPLA3‐I148M variant confers an antiatherogenic lipid profile in insulin‐resistant patients. J Clin Endocrinol Metab. 2021;106:e300–e315. doi: 10.1210/clinem/dgaa729 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0059] 59. Pelusi S, Baselli G, Pietrelli A, Dongiovanni P, Donati B, McCain MV, Meroni M, Fracanzani AL, Romagnoli R, Petta S, et al. Rare pathogenic variants predispose to hepatocellular carcinoma in nonalcoholic fatty liver disease. Sci Rep. 2019;9:3682. doi: 10.1038/s41598-019-39998-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0060] 60. Jamialahmadi O, De Vincentis A, Tavaglione F, Malvestiti F, Li‐Gao R, Mancina RM, Alvarez M, Gelev K, Maurotti S, Vespasiani‐Gentilucci U, et al. Partitioned polygenic risk scores identify distinct types of metabolic dysfunction‐associated steatotic liver disease. Nat Med. 2024;30:3614–3623. doi: 10.1038/s41591-024-03284-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0061] 61. Chow JD, Jones ME, Prelle K, Simpson ER, Boon WC. A selective estrogen receptor α agonist ameliorates hepatic steatosis in the male aromatase knockout mouse. J Endocrinol. 2011;210:323–334. doi: 10.1530/joe-10-0462 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0062] 62. Cherubini A, Ostadreza M, Jamialahmadi O, Pelusi S, Rrapaj E, Casirati E, Passignani G, Norouziesfahani M, Sinopoli E, Baselli G, et al. Interaction between estrogen receptor‐α and PNPLA3 p.I148M variant drives fatty liver disease susceptibility in women. Nat Med. 2023;29:2643–2655. doi: 10.1038/s41591-023-02553-8 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0063] 63. Jia Y, Yee JK, Wang C, Nikolaenko L, Diaz‐Arjonilla M, Cohen JN, French SW, Liu PY, Lue Y, Lee WP, et al. Testosterone protects high‐fat/low‐carbohydrate diet‐induced nonalcoholic fatty liver disease in castrated male rats mainly via modulating endoplasmic reticulum stress. Am J Physiol‐Endocrinol Metab. 2018;314:E366–e376. doi: 10.1152/ajpendo.00124.2017 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0064] 64. Nash E, Nicoll A, Batt N, George J, Perananthan V, Prince D, Wallace M, Gow P, Vaz K, Chitturi S, et al. Drug‐induced liver injury from selective androgen receptor modulators, anabolic‐androgenic steroids and bodybuilding supplements in Australia. Aliment Pharmacol Ther. 2024;59:953–961. doi: 10.1111/apt.17906 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0065] 65. Navarro G, Allard C, Morford JJ, Xu W, Liu S, Molinas AJ, Butcher SM, Fine NH, Blandino‐Rosano M, Sure VN, et al. Androgen excess in pancreatic β cells and neurons predisposes female mice to type 2 diabetes. JCI Insight. 2018;3:e98607. doi: 10.1172/jci.insight.98607 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0066] 66. Rinella ME, Neuschwander‐Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S, Barb D, Kleiner DE, Loomba R. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77:1797–1835. doi: 10.1097/hep.0000000000000323 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0067] 67. Wu H. European association for the study of the liver (EASL) congress 2024. Lancet Reg Health Eur. 2024;43:100980. doi: 10.1016/j.lanepe.2024.100980 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0068] 68. Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R, Labriola D, Moussa SE, Neff GW, Rinella ME, et al. A phase 3, randomized, controlled trial of Resmetirom in NASH with liver fibrosis. N Engl J Med. 2024;390:497–509. doi: 10.1056/NEJMoa2309000 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0069] 69. Hamasaki M, Sakane N, Kotani K. Nonalcoholic fatty liver disease risk and proprotein convertase subtilisin Kexin 9 in familial hypercholesterolemia under statin treatment. Nutrients. 2024;16:3686. doi: 10.3390/nu16213686 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0070] 70. Dai W, Xu B, Li P, Weng J. Statins for the treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: a systematic review and meta‐analysis. Am J Ther. 2023;30:e17–e25. doi: 10.1097/mjt.0000000000001499 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0071] 71. Zou B, Odden MC, Nguyen MH. Statin use and reduced hepatocellular carcinoma risk in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2023;21:435–444.e436. doi: 10.1016/j.cgh.2022.01.057 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0072] 72. Yoo J, Jeon J, Baik M, Kim J. Effect of statins for primary prevention of cardiovascular disease according to the fatty liver index. J Epidemiol Glob Health. 2024;14:710–719. doi: 10.1007/s44197-024-00205-9 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0073] 73. Zhang S, Ren X, Zhang B, Lan T, Liu B. A systematic review of statins for the treatment of nonalcoholic steatohepatitis: safety, efficacy, and mechanism of action. Molecules. 2024;29:1859. doi: 10.3390/molecules29081859 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0074] 74. Khan SU, Yedlapati SH, Lone AN, Hao Q, Guyatt G, Delvaux N, Bekkering GET, Vandvik PO, Riaz IB, Li S, et al. PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta‐analysis. BMJ. 2022;377:e069116. doi: 10.1136/bmj-2021-069116 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0075] 75. Castellano‐Castillo D, Núñez‐Sánchez M, Balaguer‐Román A, Martínez‐Sánchez MA, Fernández‐Ruiz VE, Ferrer‐Gómez M, Martínez CM, Frutos MD, Queipo‐Ortuño MI, Cardona F, et al. The role of PCSK9 in metabolic dysfunction‐associated steatotic liver disease and its impact on bariatric surgery outcomes. Surg Obes Relat Dis. 2024;20:652–659. doi: 10.1016/j.soard.2024.01.017 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0076] 76. Lee S, Zhang C, Liu Z, Klevstig M, Mukhopadhyay B, Bergentall M, Cinar R, Ståhlman M, Sikanic N, Park JK, et al. Network analyses identify liver‐specific targets for treating liver diseases. Mol Syst Biol. 2017;13:938. doi: 10.15252/msb.20177703 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0077] 77. Lebeau PF, Byun JH, Platko K, Al‐Hashimi AA, Lhoták Š, MacDonald ME, Mejia‐Benitez A, Prat A, Igdoura SA, Trigatti B, et al. Pcsk9 knockout exacerbates diet‐induced non‐alcoholic steatohepatitis, fibrosis and liver injury in mice. JHEP Rep. 2019;1:418–429. doi: 10.1016/j.jhepr.2019.10.009 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0078] 78. Sachan V, Susan‐Resiga D, Lam K, Seidah NG. The biology and clinical implications of PCSK7. Endocr Rev. 2025;46:281–299. doi: 10.1210/endrev/bnae031 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0079] 79. Krishnan A, Schneider CV, Hadi Y, Mukherjee D, AlShehri B, Alqahtani SA. Cardiovascular and mortality outcomes with GLP‐1 receptor agonists vs other glucose‐lowering drugs in individuals with NAFLD and type 2 diabetes: a large population‐based matched cohort study. Diabetologia. 2024;67:483–493. doi: 10.1007/s00125-023-06057-5 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0080] 80. Morieri ML, Targher G, Lapolla A, D'Ambrosio M, Tadiotto F, Rigato M, Frison V, Paccagnella A, Simioni N, Avogaro A, et al. Changes in markers of hepatic steatosis and fibrosis in patients with type 2 diabetes during treatment with glucagon‐like peptide‐1 receptor agonists. A multicenter retrospective longitudinal study. Nutr Metab Cardiovasc Dis. 2021;31:3474–3483. doi: 10.1016/j.numecd.2021.08.049 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0081] 81. Mantovani A, Petracca G, Beatrice G, Csermely A, Lonardo A, Targher G. Glucagon‐like Peptide‐1 receptor agonists for treatment of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: an updated meta‐analysis of randomized controlled trials. Metabolites. 2021;11:73. doi: 10.3390/metabo11020073 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0082] 82. Marso SP, Daniels GH, Brown‐Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–322. doi: 10.1056/NEJMoa1603827 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0083] 83. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, Probstfield J, Riesmeyer JS, Riddle MC, Rydén L, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double‐blind, randomised placebo‐controlled trial. Lancet. 2019;394:121–130. doi: 10.1016/s0140-6736(19)31149-3 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0084] 84. Green JB, Hernandez AF, D'Agostino RB, Granger CB, Janmohamed S, Jones NP, Leiter LA, Noronha D, Russell R, Sigmon K, et al. Harmony outcomes: a randomized, double‐blind, placebo‐controlled trial of the effect of albiglutide on major cardiovascular events in patients with type 2 diabetes mellitus‐rationale, design, and baseline characteristics. Am Heart J. 2018;203:30–38. doi: 10.1016/j.ahj.2018.03.030 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0085] 85. Seghieri M, Christensen AS, Andersen A, Solini A, Knop FK, Vilsbøll T. Future perspectives on GLP‐1 receptor agonists and GLP‐1/glucagon receptor Co‐agonists in the treatment of NAFLD. Front Endocrinol. 2018;9:649. doi: 10.3389/fendo.2018.00649 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0086] 86. Yu X, Hao M, Liu Y, Ma X, Lin W, Xu Q, Zhou H, Shao N, Kuang H. Liraglutide ameliorates non‐alcoholic steatohepatitis by inhibiting NLRP3 inflammasome and pyroptosis activation via mitophagy. Eur J Pharmacol. 2019;864:172715. doi: 10.1016/j.ejphar.2019.172715 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0087] 87. Alam S, Ghosh J, Mustafa G, Kamal M, Ahmad N. Effect of sitagliptin on hepatic histological activity and fibrosis of nonalcoholic steatohepatitis patients: a 1‐year randomized control trial. Hepatol Med Policy. 2018;10:23–31. doi: 10.2147/hmer.S158053 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0088] 88. Wang X, Hausding M, Weng SY, Kim YO, Steven S, Klein T, Daiber A, Schuppan D. Gliptins suppress inflammatory macrophage activation to mitigate inflammation, fibrosis, oxidative stress, and vascular dysfunction in models of nonalcoholic steatohepatitis and liver fibrosis. Antioxid Redox Signal. 2018;28:87–109. doi: 10.1089/ars.2016.6953 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0089] 89. Yan J, Yao B, Kuang H, Yang X, Huang Q, Hong T, Li Y, Dou J, Yang W, Qin G, et al. Liraglutide, sitagliptin, and insulin glargine added to metformin: the effect on body weight and intrahepatic lipid in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Hepatology. 2019;69:2414–2426. doi: 10.1002/hep.30320 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0090] 90. Panico C, Bonora B, Camera A, Chilelli NC, Prato GD, Favacchio G, Grancini V, Resi V, Rondinelli M, Zarra E, et al. Pathophysiological basis of the cardiological benefits of SGLT‐2 inhibitors: a narrative review. Cardiovasc Diabetol. 2023;22:164. doi: 10.1186/s12933-023-01855-y [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0091] 91. Nasiri‐Ansari N, Nikolopoulou C, Papoutsi K, Kyrou I, Mantzoros CS, Kyriakopoulos G, Chatzigeorgiou A, Kalotychou V, Randeva MS, Chatha K, et al. Empagliflozin attenuates non‐alcoholic fatty liver disease (NAFLD) in high fat diet fed ApoE((−/−)) mice by activating autophagy and reducing ER stress and apoptosis. Int J Mol Sci. 2021;22:818. doi: 10.3390/ijms22020818 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0092] 92. Lee TM, Chang NC, Lin SZ. Dapagliflozin, a selective SGLT2 inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic Biol Med. 2017;104:298–310. doi: 10.1016/j.freeradbiomed.2017.01.035 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0093] 93. Schoeler M, Caesar R. Dietary lipids, gut microbiota and lipid metabolism. Rev Endocr Metab Disord. 2019;20:461–472. doi: 10.1007/s11154-019-09512-0 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0094] 94. Fu Y, Wang Y, Gao H, Li D, Jiang R, Ge L, Tong C, Xu K. Associations among dietary Omega‐3 polyunsaturated fatty acids, the gut microbiota, and intestinal immunity. Mediat Inflamm. 2021;2021:8879227–8879211. doi: 10.1155/2021/8879227 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0095] 95. Aron‐Wisnewsky J, Warmbrunn MV, Nieuwdorp M, Clément K. Nonalcoholic fatty liver disease: modulating gut microbiota to improve severity? Gastroenterology. 2020;158:1881–1898. doi: 10.1053/j.gastro.2020.01.049 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0096] 96. du Preez R, Wanyonyi S, Mouatt P, Panchal SK, Brown L. Saskatoon berry Amelanchier alnifolia regulates glucose metabolism and improves cardiovascular and liver signs of diet‐induced metabolic syndrome in rats. Nutrients. 2020;12:931. doi: 10.3390/nu12040931 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0097] 97. Lu Z, Liu L, Zhao S, Zhao J, Li S, Li M. Apigenin attenuates atherosclerosis and non‐alcoholic fatty liver disease through inhibition of NLRP3 inflammasome in mice. Sci Rep. 2023;13:7996. doi: 10.1038/s41598-023-34654-2 [DOI] [PMC free article] [PubMed] [Google Scholar]

[jah311333-bib-0098] 98. Hu W, Li M, Sun W, Li Q, Xi H, Qiu Y, Wang R, Ding Q, Wang Z, Yu Y, et al. Hirsutine ameliorates hepatic and cardiac insulin resistance in high‐fat diet‐induced diabetic mice and in vitro models. Pharmacol Res. 2022;177:105917. doi: 10.1016/j.phrs.2021.105917 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0099] 99. Maurotti S, Pujia R, Ferro Y, Mare R, Russo R, Coppola A, Gazzaruso C, Montalcini T, Pujia A, Paone S, et al. A nutraceutical with Citrus bergamia and Cynara cardunculus improves endothelial function in adults with non‐alcoholic fatty liver disease. Nutrition. 2024;118:112294. doi: 10.1016/j.nut.2023.112294 [DOI] [PubMed] [Google Scholar]

[jah311333-bib-0100] 100. Hu S, Hu Y, Yan W. Extracellular vesicle‐mediated interorgan communication in metabolic diseases. Trends Endocrinol Metab. 2023;34:571–582. doi: 10.1016/j.tem.2023.06.002 [DOI] [PubMed] [Google Scholar]

PERMALINK

Hepatic Mechanisms of Myocardial Infarction: A New Perspective in Metabolic Dysfunction‐Associated Fatty Liver Disease

Jing Cui, MD, PhD

Wenting Wang, MD, PhD

Qian Xu, MD, PhD

Mengmeng Zhu, MD, PhD

Yiwen Li, MD, PhD

Yanfei Liu, MD, PhD

Yue Liu, MD, PhD

Abstract

Nonstandard Abbreviations and Acronyms

METABOLIC HOMEOSTASIS IMBALANCE: A CRITICAL BRIDGE BETWEEN MAFLD AND MI

Figure 1. Pathologic mechanisms of coronary heart disease due to nonalcoholic fatty liver disease.

SIGNIFICANCE OF METABOLIC INFLAMMATION IN MAFLD AND MI

CYTOKINES AND EXTRACELLULAR VESICLES MEDIATE DIRECT “HEART–LIVER” DIALOGUE IN MAFLD AND MI

BIDIRECTIONAL ROLE OF GUT MICROBIOTA IN MAFLD AND MI

ROLE OF PROTEIN METABOLISM IN MAFLD AND MI

Figure 2. Influence of hepatic genetic variation and secreted proteins on atherosclerosis and vascular endothelium.

THE ROLE OF GENETIC FACTORS IN MAFLD AND MI

CORRECTING METABOLIC DISORDERS: “COBENEFITS” FOR HEART AND LIVER

Table 1.

Table 2.

CONCLUSIONS

Sources of Funding

Disclosures

Acknowledgments

References

ACTIONS

PERMALINK

RESOURCES

Cite

Add to Collections

PERMALINK

Hepatic Mechanisms of Myocardial Infarction: A New Perspective in Metabolic Dysfunction‐Associated Fatty Liver Disease

Jing Cui, MD, PhD

Wenting Wang, MD, PhD

Qian Xu, MD, PhD

Mengmeng Zhu, MD, PhD

Yiwen Li, MD, PhD

Yanfei Liu, MD, PhD

Yue Liu, MD, PhD

Abstract

Nonstandard Abbreviations and Acronyms

METABOLIC HOMEOSTASIS IMBALANCE: A CRITICAL BRIDGE BETWEEN MAFLD AND MI

Figure 1. Pathologic mechanisms of coronary heart disease due to nonalcoholic fatty liver disease.

SIGNIFICANCE OF METABOLIC INFLAMMATION IN MAFLD AND MI

CYTOKINES AND EXTRACELLULAR VESICLES MEDIATE DIRECT “HEART–LIVER” DIALOGUE IN MAFLD AND MI

BIDIRECTIONAL ROLE OF GUT MICROBIOTA IN MAFLD AND MI

ROLE OF PROTEIN METABOLISM IN MAFLD AND MI

Figure 2. Influence of hepatic genetic variation and secreted proteins on atherosclerosis and vascular endothelium.

THE ROLE OF GENETIC FACTORS IN MAFLD AND MI

CORRECTING METABOLIC DISORDERS: “COBENEFITS” FOR HEART AND LIVER

Table 1.

Table 2.

CONCLUSIONS

Sources of Funding

Disclosures

Acknowledgments

References

ACTIONS

PERMALINK

RESOURCES

Similar articles

Cited by other articles

Links to NCBI Databases