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. 2023 Sep 28;30(12):1751–1758. doi: 10.5551/jat.RV22011

The Impact of Ketone Body Metabolism on Mitochondrial Function and Cardiovascular Diseases

Yuichiro Arima 1
PMCID: PMC10703571  PMID: 37766574

Abstract

Ketone bodies, consisting of beta-hydroxybutyrate, acetoacetate, and acetone, are metabolic byproducts known as energy substrates during fasting. Recent advancements have shed light on the multifaceted effects of ketone body metabolism, which led to increased interest in therapeutic interventions aimed at elevating ketone body levels. However, excessive elevation of ketone body concentration can lead to ketoacidosis, which may have fatal consequences. Therefore, in this review, we aimed to focus on the latest insights on ketone body metabolism, particularly emphasizing its association with mitochondria as the primary site of interaction. Given the distinct separation between ketone body synthesis and breakdown pathways, we provide an overview of each metabolic pathway. Additionally, we discuss the relevance of ketone bodies to conditions such as nonalcoholic fatty liver disease or nonalcoholic steatohepatitis and cardiovascular diseases. Moreover, we explore the utilization of ketone body metabolism, including dietary interventions, in the context of aging, where mitochondrial dysfunction plays a crucial role. Through this review, we aim to present a comprehensive understanding of ketone body metabolism and its intricate relationship with mitochondrial function, spanning the potential implications in various health conditions and the aging process.

Keywords: Ketone body metabolism, Cardiovascular diseases, Aging, Mitochondria

Introduction

Ketone bodies are composed of three metabolites, namely, beta-hydroxybutyrate, acetoacetate, and acetone 1) . Historically, ketone bodies were considered as intermediate metabolites formed during the beta-oxidation of fatty acids. However, it was later discovered that they are metabolites generated through pathways distinct from fatty acids, thus attracting attention to their physiological functions 2) . In particular, they are noted to exhibit unique characteristics as compared to other energy substrates, as their blood concentration increases during fasting and they become the primary energy substrate for the brain during periods of starvation. The role of ketone bodies as energy substrates during fasting has been widely recognized 3 , 4) . This utilization as an energy substrate during starvation is not limited to humans but is common among other species as well. Studies using birds have shown that in the initial few days after fasting stimulus, reliance is placed on lipid-derived energy substrates, but subsequently, energy supply is maintained through the elevation of beta-hydroxybutyrate levels 5) .

Ketone body metabolism has traditionally been considered primarily in terms of its role as an energy substrate. However, in recent years, it has become evident that ketone bodies are also involved in signal transduction and epigenome regulation, highlighting their multifaceted effects 1) . Furthermore, it has been discovered that ketone body synthesis and degradation take place within the mitochondria, emphasizing the close relationship between ketone body metabolism and mitochondrial function. Therefore, it has become crucial to investigate the connection between ketone body metabolism and mitochondrial function in order to fully understand ketone body metabolism 6) .

Ketone bodies are known to cause ketosis or ketoacidosis when excessively accumulated, making it a particularly serious complication in individuals with diabetes 7 , 8) . On the other hand, clinical trials aiming to harness the organ-protective effects of mild ketone elevation and the potential for extending healthy lifespan through fasting or calorie restriction-induced ketosis have also gained attention. To properly understand these phenomena, it is crucial to focus on the processes occurring in the mitochondria and gain a comprehensive understanding of the effects brought about by ketone body metabolism 9 - 11) .

Ketone Body Metabolism

The most significant characteristic of ketone body metabolism is the clear distinction between synthesizing organs, such as the liver, and consuming organs, such as the heart and brain. These differences are brought about by variations in the expression of rate-limiting enzymes within the mitochondria. Ketogenesis is known to be regulated by the expression of hydroxymethylglutaryl coenzyme A synthase 2 (Hmgcs2), whereas ketone body utilization is controlled by the expression of succinyl-CoA:3-oxoacid CoA-transferase (SCOT) ( Figs.1 and 2 ) 12 - 14) .

Fig.1. Ketone body utilization.

Fig.1. Ketone body utilization

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Ketone bodies are converted into acetyl-CoA and act as energy substrates by entering the TCA cycle.

AcAc, acetoacetate; AcAc-CoA, acetoacetyl-CoA; βOHB, β-hydroxybutyrate; NAD, nicotinamide adenine dinucleotide; SCOT, succinyl-CoA:3-ketoacid CoA-transferase; TCA, tricarboxylic acid cycle

Fig.2. Ketone body production.

Fig.2. Ketone body production

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HMG-CoA synthase 2 (Hmgcs2), a mitochondrion-localized protein, serves as the rate-limiting enzyme in ketone body synthesis. AcAc, acetoacetate; AcAc-CoA, acetoacetyl-CoA; βOHB, β-hydroxybutyrate; NAD, nicotinamide adenine dinucleotide

The substrate of ketone bodies is acetyl-CoA. Within the mitochondria, acetyl-CoA is synthesized from molecules to form acetoacetyl-CoA. Subsequently, acetoacetyl-CoA and acetyl-CoA condense through the action of HMGCS2, leading to the synthesis of hydroxymethylglutaryl coenzyme A (HMG-CoA). HMG-CoA is then converted by hydroxymethylglutaryl coenzyme A lyase into acetyl-CoA and acetoacetate. Acetoacetate is further reduced by β-hydroxybutyrate dehydrogenase (BDH1), resulting in the formation of β-hydroxybutyrate (βOHB) 15) . The reduction reaction from acetoacetyl-CoA to β-hydroxybutyrate (βOHB) involves the concomitant reduction of NADH to NAD+. Unlike HMGCS2, this reaction is reversible, and the equilibrium state is determined by the ratio of acetoacetate to β-hydroxybutyrate and the ratio of NAD+ to NADH. In other words, an increase in the amount of NADH promotes the reduction reaction, while an increase in the amount of NAD+ promotes the oxidation reaction. This equilibrium state regulates the interconversion of acetoacetate and βOHB in ketone body metabolism, adapting to the energy supply demand 16) . Additionally, a portion of acetoacetate is spontaneously decarboxylated to form acetone, which is then excreted in exhaled breath.

Acetoacetate and βOHB synthesized in the mitochondria are released into the extracellular space and reach the bloodstream through monocarboxylate transporters 17) . Monocarboxylate transporters play an important role not only in the release of ketone bodies but also in their uptake. Solute carrier family 16a, member 6 (SLC16A6), is a type of monocarboxylate transporter known to be vital in the release of ketone bodies. In a study analyzing a loss-of-function model in zebrafish, it was observed that the accumulation of β-hydroxybutyric acid in the liver led to an exacerbation of hepatosteatosis 18) . Monocarboxylate transporters also play a crucial role in the uptake of ketone bodies; in fact, genetic analysis of patients experiencing severe ketoacidosis has revealed the presence of a frameshift mutation in the solute carrier family 16a, member 1 (SLC16A1), also known as monocarboxylate transporter 1 (MCT1) 19) .

Ketone body oxidation occurs not only in the liver but also in skeletal muscles, the brain, and the heart, where it is utilized as an energy substrate 20 - 22) . The ketone bodies taken up into cells are oxidized again when they are utilized as energy substrates. The enzymes responsible for the oxidation of these ketone bodies are BDH1 and SCOT. BDH1 also functions in ketone body synthesis, but during the breakdown process, it oxidizes β-hydroxybutyrate to convert it into acetoacetate. Subsequently, through a reaction mediated by SCOT, acetoacetate is converted to acetoacetyl-CoA.

Ketone Body Utilization and Mitochondrial Function

Ketone bodies require reactions within the mitochondria for both synthesis and degradation. Here, we will introduce insights into the utilization of ketone bodies and mitochondrial function, focusing on the data obtained from the human heart ( Fig.1 ) . There are various methods to measure the utilization rate of ketone bodies, such as directly measuring ketone bodies in cardiac tissue or analyzing ketone bodies labeled with isotopic carbon 23 , 24) . However, applying these methods to a beating human heart is challenging and not commonly done. One useful method in this regard is the measurement technique utilizing blood sampling obtained during cardiac catheterization. Arterial and venous blood sampling during cardiac catheterization is a method developed to obtain metabolic evidence of myocardial ischemia. Catheters are placed in the aortic root and coronary sinus, respectively, and sampling is performed before and after the induction test for myocardial ischemia to measure the lactate production rate in the event of ischemia 25) . When myocardial ischemia occurs, anaerobic metabolism is enhanced, which then results in increased lactate production. This can be confirmed by the elevation of lactate concentration in the coronary sinus. However, this sampling method allows for the measurement of various metabolic byproducts other than lactate. By evaluating the difference between arterial and venous blood, it is possible to detect changes in metabolic status.

To elucidate the impact of mitochondrial function on ketone body utilization, we measured ketone bodies along with lactate in patients who have underwent cardiac catheterization for the diagnosis of coronary spastic angina. As a result, we confirmed that the utilization rate of ketone bodies significantly decreases during conditions of myocardial ischemia accompanied by ST elevation and increased lactate production. Furthermore, we observed a prompt recovery of the utilization rate upon alleviation of ischemia 26) . This finding indicates that aerobic metabolism in mitochondria is essential for the utilization of ketone bodies. It highlights the close relationship between the maintenance of mitochondrial function and the utilization of ketone bodies.

The utilization rate of ketone bodies is known to vary in pathological conditions other than ischemic heart disease. In diabetes, where mitochondrial function is generally believed to decline, the utilization rate of glucose and lactate decreases, while the utilization rate of ketone bodies increases 27) . In addition, in a study examining the production and consumption of metabolites in the heart using metabolomics analysis, an increased utilization rate of ketone bodies was noted in cases with reduced cardiac contractility 28) . Both diabetes and heart failure are generally believed to be associated with a decline in mitochondrial function. However, it is interesting to note that unlike cases with significantly enhanced anaerobic metabolism, the utilization rate of ketone bodies increases. In studies comparing the efficiency of oxygen utilization and energy production in the utilization of energy substrates, it is known that ketone bodies produce more ATP than glucose while consuming less oxygen per molecule as compared to the breakdown of fatty acids, making them efficient energy substrates 29 , 30) . Analysis of the changes in handling energy substrates in situations where mild to moderate mitochondrial function is impaired is expected to receive attention in the future.

Ketone Body Production and Mitochondrial Function

The synthesis of ketone bodies has been found to have multifaceted roles in addition to its function of supplying ketone bodies to other organs ( Fig.2 ) . Hmgcs2 is expressed not only in liver cells but also in the proximal tubules of the kidney and intestinal stem cells. In the intestine, intestinal stem cells expressing Hmgcs2 possess ketone body synthesis capability. They control NOTCH signaling through the inhibitory effect of β-hydroxybutyric acid on histone deacetylase, thereby maintaining stem cell function 31) . In the kidney, it has been reported that ketone bodies exert a renal protective effect by suppressing excessive activation of mTORC1 in a diabetic nephropathy model 32) . These results reveal the cellular and organ-protective effects of ketone body synthesis.

In order to elucidate the physiological significance of ketone body synthesis in the liver, we established a knockout mouse model (Hmgcs2 KO) lacking Hmgcs2, which is the rate-limiting enzyme in ketone body synthesis. Interestingly, despite being unable to synthesize ketone bodies, the Hmgcs2 KO mice are deemed viable and exhibit fasting tolerance. Evolutionarily, it has also been revealed that certain species, such as elephants and dolphins, have lost Hmgcs2 during the course of evolution, suggesting that ketone bodies may not be essential as an energy substrate during periods of starvation 33) .

On the other hand, mice with impaired ketone body synthesis exhibit rapid progression of fatty liver after birth, characterized by typical histological findings of microvesicular hepatosteatosis. Investigations using isolated liver cells have confirmed a decrease in oxygen consumption in Hmgcs2 KO mice, which indicates impaired mitochondrial function in the absence of ketone body synthesis. Ketone body synthesis utilizes acetyl-CoA as a substrate, and the deficiency in ketone body synthesis leads to the accumulation of acetyl-CoA within the cells. As a result, it has been shown that acetylation, a post-translational modification, occurs on mitochondrial proteins, inhibiting their enzymatic activity. The series of research results indicate that ketone body synthesis itself serves to alleviate excessive ketone accumulation within cells and protects mitochondrial function ( Fig.3 ) 6) .

Fig.3. Loss of ketone body production impairs mitochondrial function.

Fig.3. Loss of ketone body production impairs mitochondrial function

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When ketogenesis is impaired, the substrate acetyl-CoA accumulates. This accumulated acetyl-CoA then leads to ectopic fat deposition through de novo lipogenesis, and within the mitochondria, excessive protein acetylation progresses, causing functional impairment. AcAc, acetoacetate; AcAc-CoA, acetoacetyl-CoA; βOHB, β-hydroxybutyrate; NAD, nicotinamide adenine dinucleotide

Ketone Body Metabolism and NAFLD

The pathogenesis of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) has been found to be closely associated with mitochondrial dysfunction 34) . In a study comparing the expression patterns of mitochondrial localization genes, it was revealed that the expression of Hmgcs2 was found to decrease in NASH as compared to NAFLD 35) . In studies using antisense oligonucleotides of Hmgcs2 in adult mice, it has been shown that the progression of NAFLD/NASH induced by a high-fat diet is exacerbated by ketogenesis impairment 36 , 37) . In investigations using Hmgcs2 knockout mice, significant ectopic fat deposition was observed during the juvenile period, even under normal diet conditions, but the disease was alleviated after weaning 6) . Additionally, while histopathological findings during the juvenile period showed microvesicular ectopic fat deposition, the adult disease model exhibited a characteristic increase in macrovesicular ectopic fat deposition.

Mitochondria have been recognized as potential therapeutic targets in various diseases, including atherosclerosis 38) . Enhancing ketogenesis has been expected to alleviate excessive de novo lipogenesis and improve mitochondrial protein function. Therefore, therapeutic approaches targeting the enhancement of ketogenesis are also being investigated for the treatment of NAFLD/NASH. Studies using adenovirus vectors have demonstrated that enhancing the expression of Hmgcs2 in the liver leads to a significant reduction in ectopic fat deposition 39) . Furthermore, dietary interventions known to indirectly induce ketogenesis have been gaining attention for their potential association with NAFLD/NASH pathogenesis 40) . In humans, practicing alternative day fasting, which involves alternating “fast days” with a calorie intake of 600 kcal/day and “feast days” with unrestricted eating, for a period of 3 months has been shown to lead to weight loss, improvement in fatty liver, as well as improvement in insulin sensitivity and reduction in liver injury markers 41) .

Ketone Body Metabolism and Cardiovascular Diseases

In heart failure patients, the blood concentration of ketone bodies increases, and the utilization of ketone bodies within the myocardium also increases 23 , 28 , 42 , 43) . In studies using mice, it has been demonstrated that cardiac-specific SCOT knockout exacerbates cardiac hypertrophy induced by the transverse aortic constriction (TAC) model due to impaired ketone body utilization in the myocardium 44) . On the other hand, studies using an overexpression model of BDH1, which promotes the oxidation of ketone bodies, have reported that heart failure is alleviated by treatment with TAC; this suggests the potential of promoting the utilization of ketone bodies as a means of preventing heart failure progression 45) . Several mechanisms have been reported as the basis for the effects of ketone bodies on heart failure. As an energy substrate, metabolic reprogramming occurs with the progression of heart failure, shifting from fatty acid oxidation to a glycolysis. The addition of ketone bodies suppresses the utilization of glucose derived from heart failure and increases energy production efficiency 46) . In addition, there have been reports suggesting that β-hydroxybutyrate, among ketone bodies, inhibits the activation of the NLRP3 inflammasome and exerts a cardioprotective effect through its anti-inflammatory properties 47) .

The cardioprotective effects of ketone body supplementation has been investigated in humans as well 10) . In a study investigating the short-term effects of intravenous administration of β-hydroxybutyrate in patients with heart failure with reduced ejection fraction, improvements in terms of cardiac output and myocardial external energy efficiency were reported 48) . However, reports from another group have also indicated that although the utilization rate of ketone bodies increases, it may not lead to improvements in terms of cardiac function 49) . Further investigation is thus necessary to clarify this matter. To achieve medium- to long-term ketone body supplementation, approaches such as the use of ketone salts and ketone esters and supplementation of medium-chain fatty acids are being explored 50) . In models of chronic supplementation of ketone esters, it has been demonstrated that the decline in cardiac function induced by TAC is alleviated 51) .

The cardioprotective effects of ketone body supplementation are not only anticipated for heart failure but also for myocardial ischemia. A report from Japan in 2002 demonstrated the reduction in infarct size with supplementation of β-hydroxybutyrate 52) . However, there have been lacking subsequent reports on this topic for a long period of time. Indeed, in recent times, the increased ketone body metabolism induced by the administration of sodium–glucose linked transporter inhibitors (SGLT2i) has also become a focus of research. The actual effect of SGLT2 inhibitors on myocardial infarction has been confirmed to reduce the size of the infarction when administered. Similarly, a comparable effect has also been observed with ketone supplementation 53) .

Ketone Body Metabolism and Aging

The function of mitochondria has been closely related to aging 54) . In recent years, the beneficial effects of calorie restriction and fasting on extending healthy lifespan have become evident, and there is also growing interest in ketone metabolism 55) . In this context, it has been demonstrated that a ketogenic diet extends both longevity and healthspan of adult mice 56) . Furthermore, a ketogenic diet has been shown to improve cognitive function in aging mice 57) . Recently, investigation using Hmgcs2 KO mice has also been reported in Japan 58) . In Hmgcs2 KO mice, a reduction in maximum lifespan has been observed, but lifespan extension effects were obtained through administration of 1,3-butanediol, which is the precursor of ketone bodies. On the other hand, in mouse models where 1,3-butanediol or a ketogenic diet was administered from an early stage to wild-type mice, lifespan was shortened as compared to wild-type mice. However, in models where dietary intervention started at 72 weeks of age, the lifespan extension effect of 1,3-butanediol was observed. Investigations using ApoE-deficient mice, which are commonly used as a model for atherosclerosis, showed that both 1,3-butanediol and a ketogenic diet shortened lifespan. These series of results have revealed the importance of endogenous ketone bodies and the differential responsiveness based on the timing of intervention and the pathological condition. Recently, in time-restricted eating, which increases ketone body levels through fasting, reports have shown that it leads to early disease progression in atherosclerosis mouse models, indicating the need for further investigation regarding dietary interventions 59) .

Conclusion

In this review, we have provided an overview of the multifaceted effects of ketone metabolism and the changes associated with diseases and aging from both the synthesis and breakdown pathways of ketone body metabolism. The ketone body metabolism, which has long been recognized as an energy substrate during periods of fasting, has been shown to have various effects beyond its role as an energy substrate ( Fig.4 ) . The impacts of these different effects are yet to be elucidated; thus, further analysis is needed to fully understand the implications of each action. On the other hand, it is evident that excessively high levels of ketone bodies, leading to a condition called ketoacidosis, can have negative effects on the body. Therefore, careful and meticulous research is essential when considering intervention methods related to ketone bodies. This applies not only to pharmacological approaches but also to techniques such as fasting and calorie restriction, which can induce ketone body metabolism. Understanding the appropriate means of regulating ketone body metabolism is deemed crucial in our ongoing pursuit of promoting health and longevity in society.

Fig.4. Multiple roles of ketone body metabolism.

Fig.4. Multiple roles of ketone body metabolism

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Ketone body metabolism has diverse functions beyond providing energy substrates; this includes signal transduction, epigenome regulation, and mitochondrial protection.

Conflicts of Interest

None.

References

  • 1).Puchalska P, Crawford PA. Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics. Cell Metab, 2017; 25: 262-284 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2).Krebs HA. The regulation of the release of ketone bodies by the liver. Adv Enzym Regul, 1966; 4: 339-353 [DOI] [PubMed] [Google Scholar]
  • 3).Jr. GFC. Fuel Metabolism in Starvation. Annu Rev Nutr, 2006; 26: 1-22 [DOI] [PubMed] [Google Scholar]
  • 4).Longo VD, Mattson MP. Fasting: Molecular Mechanisms and Clinical Applications. Cell Metab, 2014; 19: 181-192 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5).Maho YL, Kha HVV, Koubi H, Dewasmes G, Girard J, Ferre P, et al. Body composition, energy expenditure, and plasma metabolites in long-term fasting geese. Am J Physiol Metab, 1981; 241: E342-354 [DOI] [PubMed] [Google Scholar]
  • 6).Arima Y, Nakagawa Y, Takeo T, Ishida T, Yamada T, Hino S, et al. Murine neonatal ketogenesis preserves mitochondrial energetics by preventing protein hyperacetylation. Nat Metab, 2021; 3: 196-210 [DOI] [PubMed] [Google Scholar]
  • 7).Araki E, Goto A, Kondo T, Noda M, Noto H, Origasa H, et al. Japanese Clinical Practice Guideline for Diabetes 2019. J Diabetes Investig, 2020; 11: 1020-1076 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8).Nasa P, Chaudhary S, Shrivastava PK, Singh A. Euglycemic diabetic ketoacidosis: A missed diagnosis. World J Diabetes, 2021; 12: 514-523 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9).Varady KA, Cienfuegos S, Ezpeleta M, Gabel K. Clinical application of intermittent fasting for weight loss: progress and future directions. Nat Rev Endocrinol, 2022; 18: 309-321 [DOI] [PubMed] [Google Scholar]
  • 10).Yurista SR, Chong CR, Badimon JJ, Kelly DP, Boer RA de, Westenbrink BD. Therapeutic Potential of Ketone Bodies for Patients With Cardiovascular Disease. J Am Coll Cardiol, 2021; 77: 1660-1669 [DOI] [PubMed] [Google Scholar]
  • 11).Longo VD, Anderson RM. Nutrition, longevity and disease: From molecular mechanisms to interventions. Cell, 2022; 185: 1455-1470 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12).Fenselau A, Wallis K. 3-oxo acid coenzyme A-transferase in normal and diabetic rat muscle. Biochem J, 1976; 158: 509-512 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13).Grinblat L, Bolaños LFP, Stoppani AO. Decreased rate of ketone-body oxidation and decreased activity of d -3-hydroxybutyrate dehydrogenase and succinyl-CoA: 3-oxo-acid CoA-transferase in heart mitochondria of diabetic rats. Biochem J, 1986; 240: 49-56 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14).Mascaro C, Buesa C, Ortiz JA, Hare D, Hegardt FG. Molecular Cloning and Tissue Expression of Human Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase. Arch Biochem Biophys, 1995; 317: 385-390 [DOI] [PubMed] [Google Scholar]
  • 15).LEHNINGER AL, SUDDUTH HC, WISE JB. D-beta-Hydroxybutyric dehydrogenase of muitochondria. The J biological Chem, 1960; 235: 2450-2455 [PubMed] [Google Scholar]
  • 16).Williamson D, Lund P, Krebs H. The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver. Biochem J, 1967; 103: 514-527 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17).IWANAGA T, KISHIMOTO A. Cellular distributions of monocarboxylate transporters: a review. Biomed Res, 2015; 36: 279-301 [DOI] [PubMed] [Google Scholar]
  • 18).Hugo SE, Cruz-Garcia L, Karanth S, Anderson RM, Stainier DYR, Schlegel A. A monocarboxylate transporter required for hepatocyte secretion of ketone bodies during fasting. Genes Dev, 2012; 26: 282-293 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19).M. van HP, Sacha F, R. MG, P.N. RJ, Marjolein T, J. GM, et al. Monocarboxylate Transporter 1 Deficiency and Ketone Utilization. New Engl J Medicine, 2014; 371(20): 1900-1907 [DOI] [PubMed] [Google Scholar]
  • 20).Matsuura TR, Puchalska P, Crawford PA, Kelly DP. Ketones and the Heart: Metabolic Principles and Therapeutic Implications. Circ Res, 2023; 132: 882-898 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21).García-Rodríguez D, Giménez-Cassina A. Ketone Bodies in the Brain Beyond Fuel Metabolism: From Excitability to Gene Expression and Cell Signaling. Frontiers Mol Neurosci, 2021; 14: 732120 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22).Svensson K, Albert V, Cardel B, Salatino S, Handschin C. Skeletal muscle PGC-1α modulates systemic ketone body homeostasis and ameliorates diabetic hyperketonemia in mice. FASEB J Off Publ Fed Am Soc Exp Biology, 2015; 30: 1976-1986 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23).Jr KCB, Snyder NW, Brandimarto J, Aziz M, Mesaros C, Worth AJ, et al. Evidence for Intramyocardial Disruption of Lipid Metabolism and Increased Myocardial Ketone Utilization in Advanced Human Heart Failure. Circulation, 2016; 133: 706-716 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24).Beylot M, Beaufrère B, Normand S, Riou JP, Cohen R, Momex R. Determination of human ketone body kinetics using stable-isotope labelled tracers. Diabetologia, 1986; 29: 90-96 [DOI] [PubMed] [Google Scholar]
  • 25).Ohba K, Sugiyama S, Sumida H, Nozaki T, Matsubara J, Matsuzawa Y, et al. Microvascular Coronary Artery Spasm Presents Distinctive Clinical Features With Endothelial Dysfunction as Nonobstructive Coronary Artery Disease. J Am Hear Assoc, 2012; 1: e002485 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26).Arima Y, Izumiya Y, Ishida T, Takashio S, Ishii M, Sueta D, et al. Myocardial Ischemia Suppresses Ketone Body Utilization. J Am Coll Cardiol, 2019; 73: 246-247 [DOI] [PubMed] [Google Scholar]
  • 27).Mizuno Y, Harada E, Nakagawa H, Morikawa Y, Shono M, Kugimiya F, et al. The diabetic heart utilizes ketone bodies as an energy source. Metabolism, 2017; 77: 65-72 [DOI] [PubMed] [Google Scholar]
  • 28).Murashige D, Jang C, Neinast M, Edwards JJ, Cowan A, Hyman MC, et al. Comprehensive quantification of fuel use by the failing and nonfailing human heart. Science, 2020; 370: 364-368 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29).Lopaschuk GD, Ussher JR, Folmes CDL, Jaswal JS, Stanley WC. Myocardial Fatty Acid Metabolism in Health and Disease. Physiol Rev, 2010; 90: 207-258 [DOI] [PubMed] [Google Scholar]
  • 30).Robinson AM, Williamson DH. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev, 1980; 60: 143-187 [DOI] [PubMed] [Google Scholar]
  • 31).Cheng CW, Biton M, Haber AL, Gunduz N, Eng G, Gaynor LT, et al. Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet. Cell, 2019; 178: 1115-1131.e15 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32).Tomita I, Kume S, Sugahara S, Osawa N, Yamahara K, Yasuda-Yamahara M, et al. SGLT2 Inhibition Mediates Protection from Diabetic Kidney Disease by Promoting Ketone Body-Induced mTORC1 Inhibition. Cell Metab, 2020; 32: 404-419.e6 [DOI] [PubMed] [Google Scholar]
  • 33).Jebb D, Hiller M. Recurrent loss of HMGCS2 shows that ketogenesis is not essential for the evolution of large mammalian brains. eLife, 2018; 7: e38906 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34).Loomba R, Friedman SL, Shulman GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell, 2021; 184: 2537-2564 [DOI] [PubMed] [Google Scholar]
  • 35).Bragoszewski P, Habior A, Walewska-Zielecka B, Ostrowski J. Expression of genes encoding mitochondrial proteins can distinguish nonalcoholic steatosis from steatohepatitis. Acta biochimica Polonica, 2007; 54: 341-348 [PubMed] [Google Scholar]
  • 36).d’Avignon DA, Puchalska P, Ercal B, Chang Y, Martin SE, Graham MJ, et al. Hepatic ketogenic insufficiency reprograms hepatic glycogen metabolism and the lipidome. JCI Insight, 2018; 3: e99762 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37).Cotter DG, Ercal B, Huang X, Leid JM, d’Avignon DA, Graham MJ, et al. Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia. J Clin Investig, 2014; 124: 5175-5190 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38).Dorighello GG, Rovani JC, Paim BA, Rentz T, Assis LHP, Vercesi AE, et al. Mild Mitochondrial Uncoupling Decreases Experimental Atherosclerosis, A Proof of Concept. J Atheroscler Thromb, 2022; 29: 825-838 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39).Asif S, Kim RY, Fatica T, Sim J, Zhao X, Oh Y, et al. Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis. Mol Metab, 2022; 61: 101494 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40).Minciună I, Gallage S, Heikenwalder M, Zelber-Sagi S, Dufour JF. Intermittent fasting- the future treatment in nash patients? Hepatology, 2023; Publish Ahead of Print [DOI] [PubMed] [Google Scholar]
  • 41).Ezpeleta M, Gabel K, Cienfuegos S, Kalam F, Lin S, Pavlou V, et al. Effect of alternate day fasting combined with aerobic exercise on non-alcoholic fatty liver disease: A randomized controlled trial. Cell Metab, 2023; 35: 56-70.e3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42).Lommi J, Kupari M, Koskinen P, Näveri H, Leinonen H, Pulkki K, et al. Blood ketone bodies in congestive heart failure. J Am Coll Cardiol, 1996; 28: 665-672 [DOI] [PubMed] [Google Scholar]
  • 43).Aubert G, Martin OJ, Horton JL, Lai L, Vega RB, Leone TC, et al. The Failing Heart Relies on Ketone Bodies as a Fuel. Circulation, 2016; 133: 698-705 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44).Schugar RC, Moll AR, d’Avignon DA, Weinheimer CJ, Kovacs A, Crawford PA. Cardiomyocyte-specific deficiency of ketone body metabolism promotes accelerated pathological remodeling. Mol Metab, 2014; 3: 754-769 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45).Uchihashi M, Hoshino A, Okawa Y, Ariyoshi M, Kaimoto S, Tateishi S, et al. Cardiac-Specific Bdh1 Overexpression Ameliorates Oxidative Stress and Cardiac Remodeling in Pressure Overload–Induced Heart Failure. Circ Hear Fail, 2017; 10: e004417 [DOI] [PubMed] [Google Scholar]
  • 46).Horton JL, Davidson MT, Kurishima C, Vega RB, Powers JC, Matsuura TR, et al. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI Insight, 2019; 4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47).Deng Y, Xie M, Li Q, Xu X, Ou W, Zhang Y, et al. Targeting Mitochondria-Inflammation Circuit by β-Hydroxybutyrate Mitigates HFpEF. Circ Res, 2021; 128: 232-245 [DOI] [PubMed] [Google Scholar]
  • 48).Nielsen R, Møller N, Gormsen LC, Tolbod LP, Hansson NH, Sorensen J, et al. Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients. Circulation, 2019; 139: 2129-2141 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49).Ho KL, Zhang L, Wagg C, Batran RA, Gopal K, Levasseur J, et al. Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency. Cardiovasc Res, 2019; 115: cvz045 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50).Takahara S, Soni S, Maayah ZH, Ferdaoussi M, Dyck JRB. Ketone therapy for heart failure: current evidence for clinical use. Cardiovasc Res, 2021; 118: 977-987 [DOI] [PubMed] [Google Scholar]
  • 51).Takahara S, Soni S, Phaterpekar K, Kim TT, Maayah ZH, Levasseur JL, et al. Chronic exogenous ketone supplementation blunts the decline of cardiac function in the failing heart. ESC Hear Fail, 2021; 8: 5606-5612 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 52).Zou Z, Sasaguri S, Rajesh KG, Suzuki R. dl-3-Hydroxybutyrate administration prevents myocardial damage after coronary occlusion in rat hearts. Am J Physiol Circ Physiol, 2002; 283: H1968-1974 [DOI] [PubMed] [Google Scholar]
  • 53).Santos-Gallego CG, Requena-Ibáñez JA, Picatoste B, Fardman B, Ishikawa K, Mazurek R, et al. Cardioprotective Effect of Empagliflozin and Circulating Ketone Bodies During Acute Myocardial Infarction. Circ Cardiovasc Imaging, 2023; 16: e015298 [DOI] [PubMed] [Google Scholar]
  • 54).López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell, 2023; 186: 243-278 [DOI] [PubMed] [Google Scholar]
  • 55).Longo VD, Panda S. Fasting, Circadian Rhythms, and Time-Restricted Feeding in Healthy Lifespan. Cell Metab, 2016; 23: 1048-1059 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56).Roberts MN, Wallace MA, Tomilov AA, Zhou Z, Marcotte GR, Tran D, et al. A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice. Cell Metab, 2017; 26: 539-546.e5 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57).Newman JC, Covarrubias AJ, Zhao M, Yu X, Gut P, Ng CP, et al. Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice. Cell Metab, 2017; 26: 547-557.e8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58).Tomita I, Tsuruta H, Yasuda‐Yamahara M, Yamahara K, Kuwagata S, Tanaka‐Sasaki Y, et al. Ketone bodies: A double‐edged sword for mammalian life span. Aging Cell, 2023; e13833 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59).Pan C, Herrero-Fernandez B, Almarcha CB, Bris RG, Zorita V, Sáez A, et al. Time-Restricted Feeding Enhances Early Atherosclerosis in Hypercholesterolemic Mice. Circulation, 2023; 147: 774-777 [DOI] [PubMed] [Google Scholar]

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