Lipidome remodeling in primary biliary cholangitis

Abstract

Primary biliary cholangitis (PBC) is a chronic, cholestatic liver disease characterized by progressive destruction of intrahepatic bile ducts, impaired bile flow, and complex disturbances in bile acid and lipid metabolism. PBC is associated with a distinctive dyslipidemic profile, marked by elevated total cholesterol, accumulation of lipoprotein X, and paradoxically high HDL levels. At the molecular level, dysregulation of bile acid-activated nuclear receptors - particularly farnesoid X receptor (FXR) and peroxisome proliferator-activated receptors (PPARs) - contributes to abnormalities in cholesterol turnover, lipoprotein composition, and systemic metabolic signaling. Advances in lipidomics have revealed alterations in bioactive lipid classes such as sphingolipids and acylcarnitines, suggesting their role in hepatic inflammation and fibrogenesis. While ursodeoxycholic acid remains the standard of care, adjunctive therapies such as fibrates and selective nuclear receptor agonists are under investigation for their dual lipid-modifying and anti-cholestatic effects. A deeper understanding of lipid metabolism in PBC may yield novel biomarkers and guide more individualized therapeutic approaches.

Introduction

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease that predominantly affects women and is characterized by the progressive destruction of small intrahepatic bile ducts [1, 2]. A hallmark of PBC is the presence of antimitochondrial antibodies (AMA-M2), directed against the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2). Less commonly, antinuclear antibodies such as anti-sp100 or anti-gp210 are detected, the presence of which has been associated with a more aggressive disease course [3–5].

Current concepts indicate that the initiating event in PBC is bile acid - mediated injury of small intrahepatic cholangiocytes due to failure of the biliary bicarbonate (HCO₃⁻) “umbrella”, rather than primary immune-cell cytotoxicity. Reduced HCO₃⁻ secretion by biliary epithelial cells (linked to impaired bicarbonate transport) acidifies luminal bile, promoting protonation of bile acids that can more readily traverse the apical barrier and enter small cholangiocytes. Once inside (at a more alkaline intracellular pH), bile acids deprotonate and accumulate, exerting detergent effects that disrupt cellular and organellar membranes and drive cholangiocyte apoptosis. This conceptual model also explains the predominant injury of small ducts, because large-duct cholangiocytes are additionally protected by a mucin-rich glycocalyx produced by peribiliary glands, whereas small ducts lack this mucin layer and therefore depend primarily on HCO₃⁻- based protection [1, 6]. Periductal mononuclear infiltration (including CD4⁺/CD8⁺ T cells) and cytokine-mediated amplification (e.g., IFN-γ, IL-17) are viewed mainly as downstream responses to ongoing epithelial damage and release of inflammatory mediators from injured cholangiocytes, contributing to persistence and progression of the lesion. The resulting edema and inflammation contribute to bile duct narrowing and impaired bile flow. In later stages of the disease, a reduction in the number of functioning bile ducts - ductopenia - is observed. The loss of these structures impairs the proper transport of bile, which contains hepatotoxic bile acids, leading to their accumulation in the systemic circulation. The bile acids accumulating in hepatocytes further stimulate the inflammatory process and cause additional damage to surrounding liver tissue, ultimately leading to fibrosis and cirrhosis [7–10].

The lipidome in PBC is characterized by considerable complexity, arising from the interplay between chronic cholestasis, hepatocellular dysfunction, and systemic metabolic alterations. As bile formation and secretion are central to lipid homeostasis, their impairment in PBC leads to widespread disturbances across multiple lipid classes, including phospholipids, triglycerides (TG), and cholesterol esters [11, 12]. These changes are not uniform but vary depending on disease stage, treatment status, and individual patient factors. Furthermore, the lipid profile is influenced by both hepatic and extrahepatic processes, with contributions from altered intestinal absorption, systemic inflammation, and compensatory metabolic adaptations. This multifaceted disruption of lipid metabolism underscores the importance of comprehensive lipidomic analyses to better understand the pathophysiology of PBC and identify potential diagnostic or prognostic markers.

Metabolism of bile acids

Bile acids and their salts, along with phospholipids, cholesterol, bile pigments (including bilirubin), electrolytes, and xenobiotics are the main components of bile, which plays a crucial role in digestion. Bile acids are the end product of cholesterol catabolism [13]. The primary bile acids – cholic acid and chenodeoxycholic acid – are synthesized in hepatocytes, conjugated with glycine or taurine, and subsequently secreted into bile. Once in the intestinal lumen, bile acids facilitate the digestion and absorption of dietary fats. A portion of these bile acids is converted by intestinal bacterial enzymes into secondary bile acids, such as deoxycholic acid and lithocholic acid. These secondary bile acids are subsequently reabsorbed in the ileum and transported back to the liver via the portal circulation. This mechanism, known as enterohepatic circulation, enables the recirculation of approximately 95% of bile acids, thereby minimizing their loss and ensuring their repeated utilization. The remaining fraction, approximately 5%, is excreted in the feces and resynthesized through de novo synthesis in the liver (Fig. 1) [14, 15].

Fig. 1.

Enterohepatic circulation of bile acids. Bile acids are synthesized in the liver from cholesterol, with 95% being recycled and 5% newly produced. Most bile acids (95%) are reabsorbed in the terminal ileum and return to the liver via the portal vein, 5% are excreted in the feces

Fat digestion

One of the most commonly described symptoms in PBC and other liver diseases characterized by impaired bile flow is steatorrhea, which results from disturbed fat digestion and is typically defined as fecal fat excretion exceeding 7 g per day [16]. Physiologically, bile acids reduce surface tension, facilitating the breakdown of large fat droplets into smaller ones and the formation of amphipathic structures – micelles – which increase the surface area available to digestive enzymes such as pancreatic lipase. In the absence of sufficient bile acids, the emulsification process becomes inefficient, leading to the accumulation of undigested fats in the lumen of the small intestine. Moreover, as osmotically active compounds, these fats attract water, contributing to steatorrhea, bloating, energy malnutrition, and progressive weight loss [17, 18].

Data on the prevalence of steatorrhea in PBC alone – as well as in other cholestatic liver diseases – remain limited, likely due in part to the complexity of the diagnostic process, which includes the requirement for a 72-hour stool collection preceded by a sustained high-fat diet [17]. In one study addressing steatorrhea in patients with PBC, a correlation was observed between histopathological disease progression and the presence of steatorrhea. None of the patients in stages 1 or 2 exhibited steatorrhea, whereas it was present in the majority of those in stages 3 and 4. Furthermore, fat excretion exceeding 35 g per day was documented in nearly half of these advanced-stage patients [19].

To date, no link has been demonstrated between pancreatic lipase secretion and the occurrence of steatorrhea in patients with PBC. Its slightly reduced concentration in the duodenal lumen is most likely secondary to diminished stimulation of pancreatic secretion, resulting from the decreased delivery of bile acids into the intestinal lumen [16].

Moreover, the accumulation of lipids in the gastrointestinal tract – similarly to reduced bile acid supply – has a complex and multifaceted impact on the gut microbiota, altering its composition [20]. Excessive bacterial overgrowth is also suggested to contribute to the development of steatorrhea in patients with PBC [18].

Impaired digestion and absorption of lipids are among the most significant complications of chronic cholestasis. Under physiological conditions, micelles formed through the action of bile acids and pancreatic (brush-border) lipase – containing fatty acids, monoglycerides, phospholipids, and cholesterol – are transported to the microvilli of the distal duodenum and jejunum, where they are absorbed. Subsequently, within enterocytes, these products undergo re-esterification into triglycerides and, together with phospholipids, cholesterol, and apolipoproteins, form chylomicrons. These are then transported via the lymphatic system into the bloodstream and distributed to peripheral tissues. Bile acids are secreted from enterocytes back into the intestinal lumen, where they once again participate in the emulsification and absorption of lipids. During their passage through the small intestine, bile acids undergo 4–6 such cycles [16, 17].

Disruption of this process due to bile acid deficiency leads to decreased absorption of lipids and fat-soluble vitamins, contributing to malnutrition and progressive weight loss. Fatty acids become the primary energy substrate, and activation of their β-oxidation results in a gradual depletion of adipose tissue. Moreover, liver cirrhosis itself – a state of increased catabolism – further predisposes to malnutrition and its associated complications, including sarcopenia. However, the metabolic disturbances accompanying cirrhosis extend far beyond the disturbance of lipid metabolism [21]. In advanced liver disease, symptoms such as nausea, bloating, and early satiety also contribute to reduced meal size and inadequate energy intake [22].

There are few studies addressing malnutrition in PBC and other cholestatic liver diseases. In a study by Wicks et al., conducted in the 1990s prior to the widespread use of ursodeoxycholic acid (UDCA) for PBC treatment, signs of malnutrition – assessed using methods such as mid-arm circumference and skinfold thickness – were observed in 32.5% of patients, 69.2% of whom had been diagnosed with cirrhosis [23]. This study also highlighted a marked decrease in caloric intake among patients with PBC as the disease progressed. Notably, the European Association for the Study of the Liver (EASL) guidelines on nutrition in chronic liver disease identify two major risk factors for underweight: a body mass index (BMI) less than 18.5 kg/m2 (where most cirrhotic patients exhibit sarcopenia), and having severe decompensated cirrhosis, specifically in Child-Pugh C patients [22]. Thus, malnutrition in patients with PBC – particularly in later disease stages – may result from a combination of impaired fat digestion and absorption, inadequate nutrient intake, and increased catabolism due to cirrhosis.

Unfortunately, as with data on the prevalence of steatorrhea and malnutrition in PBC, studies evaluating the effect of UDCA on fecal fat excretion are also limited. In a study by Savioli et al., involving a small cohort of patients with cirrhosis of various etiologies, a two-week course of UDCA at a dose of 300 mg per day led to a reduction in fecal fat excretion from 14.7 g to 10.6 g per day, alongside a decrease in reported dyspeptic symptoms [24]. Considering that the current standard dose of UDCA is 13–15 mg/kg/day – on average, approximately three times higher than that used in the Savioli study – it is reasonable to assume that the prevalence of steatorrhea and consequent malnutrition in PBC patients is currently relatively low.

Fat-soluble vitamins

Micelles formed by bile acids also play a crucial role in the transport of fat-soluble vitamins (A, D, E, and K), facilitating their absorption in the small intestine. However, according to available research, deficiencies of these vitamins become clinically significant only in the advanced stages of cirrhosis or in cases of prolonged jaundice, and are relatively rare in the course of PBC [25, 26]. In a study by Phillips et al., deficiencies of vitamins A, D, E, and K were identified in 33.5%, 13.2%, 1.9%, and 7.8% of patients with PBC, respectively. Notably, only the severity of vitamin A deficiency was correlated with more advanced histopathological stages of PBC and higher total cholesterol levels [25]. Measurement of vitamin A metabolites also appears to be a promising test that could potentially replace the 72-hour fecal fat excretion test, as vitamin A absorption has been shown to reflect the status of fat absorption in cases of severe malabsorption [27]. Osteodystrophy associated with PBC – referred to as hepatic osteodystrophy – results from both osteopenia and osteoporosis (disorders of bone formation) as well as osteomalacia (a disorder of bone mineralization), with an estimated prevalence of 30–40% [28]. The pathogenesis of hepatic osteodystrophy remains incompletely understood, but it is suggested that hyperbilirubinemia and bile acids exert direct effects on osteoblasts and the osteogenesis process, rather than vitamin D deficiency being the primary driver [29, 30].

According to the EASL guidelines, apart from vitamin D and calcium supplementation for the prevention of osteoporosis, routine monitoring and supplementation of vitamins A, E, and K are not recommended in patients with PBC or other cholestatic liver diseases. Such decisions should be individualized. However, intravenous or subcutaneous prophylactic administration of vitamin K is advised in patients with severe cholestasis prior to invasive procedures or in cases of active bleeding [31, 32].

Dyslipidemia

Dyslipidemia and its pathogenesis in patients with PBC are distinct from those observed in other conditions. In the early stages of the disease, elevated levels of high-density lipoprotein (HDL) are typically observed. As the disease progresses, there is a progressive increase in total cholesterol (TC), phospholipids, fatty acids, and low-density lipoprotein (LDL) levels, along with the appearance of the abnormal lipoprotein X (Lp-X). In contrast, triglyceride concentrations remain low or only slightly elevated [33, 34]. Approximately 75–80% of patients with PBC present with hypercholesterolemia at the time of diagnosis [35, 36].

Cholesterol homeostasis in the human body depends on efficient absorption, transport between peripheral tissues and the liver, and removal from the circulation. Circulating cholesterol levels increase through intestinal absorption (from diet and bile acids) and hepatic synthesis, followed by secretion into the bloodstream in the form of very low-density (VLDL) and low-density lipoproteins. The liver synthesizes approximately 1 gram of cholesterol per day, while other tissues produce it at insufficient levels and therefore rely on cholesterol delivered by LDL particles. HDL transports excess cholesterol from peripheral tissues and plasma back to the liver, where it is processed and ultimately excreted. Cholesterol elimination occurs via hepatic uptake of LDL and HDL and through conversion into bile acids – this being the primary pathway for cholesterol clearance. On average, around 500 mg of cholesterol is converted daily into bile acids in adult humans, a portion of which is excreted in the feces [11, 37, 38].

In patients with PBC, reduced bile acid delivery to the intestine impairs micelle formation and lowers intestinal cholesterol absorption; hepatic LDL receptor–mediated LDL clearance may also be reduced, as suggested by LDL apoB kinetic data, thereby contributing to dyslipidemia [39]. During cholestasis, bile acids accumulate in hepatocytes and activate hepatic FXR-dependent adaptive pathways. Bile acids delivered to the terminal ileum via the intestinal lumen activate ileal FXR and stimulate FGF19 secretion; however, reduced luminal bile acid delivery in cholestasis may blunt ileal FXR activation. In addition, human cholestatic liver (including PBC) can ectopically express FGF19, which may contribute to elevated circulating FGF19 [40–42]. FGF-19 subsequently activates FGFR4 receptors in the liver, resulting in suppression of cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid synthesis from cholesterol [43]. This negative feedback mechanism is the principal regulator of bile acid biosynthesis in humans and serves to protect the liver from the cytotoxic effects of bile acid accumulation. FXR receptors in hepatocytes further contribute to the inhibition of bile acid production (Fig. 2). Thus, the combination of reduced bile acid synthesis, increased hepatic cholesterol production, and diminished cholesterol excretion due to reduced bile flow into the intestinal lumen collectively contributes to elevated serum cholesterol levels in PBC [39, 44–46].

Fig. 2.

FXR–FGF15/19 regulatory pathway involved in bile acid homeostasis. Bile acids activate the farnesoid X receptor (FXR) in enterocytes of the small intestine. This activation leads to the production and release of fibroblast growth factor 15/19 (FGF15 in mice, FGF19 in humans) into the bloodstream. FGF15/19 travels to the liver, where it binds to the FGF receptor 4 (FGFR4) on hepatocytes. This signaling cascade inhibits CYP7A1, the key enzyme responsible for bile acid synthesis from cholesterol. Additionally, bile acids directly activate hepatic FXR, which also contributes to CYP7A1 repression. This feedback loop prevents excessive bile acid synthesis, maintaining bile acid balance and protecting hepatocytes from bile acid toxicity

A recently published study demonstrated that hypercholesterolemia – defined as a total cholesterol concentration > 200 mg/dL – is associated with a poorer prognosis in patients with PBC, including a higher risk of complications, liver transplantation, and mortality directly related to liver disease [47].

Lipoproteins

The initial increase in HDL concentration observed during the course of PBC is likely attributable to a circulating inhibitor of hepatic lipase, which reduces its activity and inhibits the catabolism of triglycerides within HDL particles [48]. In the study by Zhang et al. (2021), HDL levels in patients with PBC were found to be higher than those in individuals with other chronic liver diseases and healthy controls [49]. As the disease progresses, HDL concentrations decline but generally remain elevated.

In contrast, multiple factors contribute to the elevation of LDL levels, including a reduced number of functional hepatocytes and, consequently, a decreased number of LDL receptors [39]. However, the lipid metabolism disturbances in PBC are far more complex and, in many cases, are related to the presence of structurally abnormal lipoproteins.

Under physiological conditions, triglycerides, phospholipids, cholesterol, and fatty acids cannot circulate freely in the aqueous environment of blood. Instead, they are transported in the form of micellar or lamellar, single-layered lipoprotein particles – HDL, LDL, and VLDL. These lipoproteins are composed of amphipathic phospholipids, which arrange themselves to form a monolayer surrounding a hydrophobic core. Within this monolayer lie free (non-esterified) cholesterol molecules – constituting about 30% of total cholesterol – and apolipoproteins, which serve as molecular “tags” for receptor recognition on cell surfaces. The core of these particles contains esterified cholesterol (bound to fatty acids) and triglycerides, which account for the remaining ~ 70% of TC [37, 50, 51].

Cholesterol in bile is also present in an aqueous environment, transported via micellar or lamellar structures; however, their composition differs from those in plasma. In bile, cholesterol is present exclusively in the free (non-esterified) form and is solubilized mainly within mixed micelles and vesicles. In bile, these complexes include phospholipids and bile acids, while albumin substitutes for apolipoproteins in stabilizing the structures. This solubilization mechanism prevents cholesterol precipitation and protects biliary epithelial cells from the cytotoxic effects of bile acids. Maintaining appropriate lipid concentrations in bile – as well as the correct phospholipid-to-bile acid ratio – is essential to prevent cholesterol crystallization and the subsequent development of gallstone disease [11, 14, 52].

The regurgitation of bile acids into the systemic circulation, a hallmark of PBC, significantly disrupts the physiological processes of cholesterol transport via lipoproteins. In such cases, the concentration of free bile acids in the blood can increase up to 100-fold above normal levels. Initially, these bile acids are neutralized through binding to albumin. However, once albumin’s binding capacity is saturated, bile acids begin to associate with plasma lipoproteins (primarily LDL and HDL). At even higher concentrations, they interact directly with cell membrane components in erythrocytes and endothelial cells. By binding to phospholipids and cholesterol, bile acids form micellar and lamellar structures similar to those in bile. These interactions compromise membrane integrity and mechanical stability, alter the function of membrane-bound proteins such as transporters, receptors, and enzymes, and may disrupt essential cellular processes including ion transport and intracellular signaling. The observed increase in circulating lipoprotein levels in PBC thus represents a compensatory response aimed at protecting cellular membranes from lipid degradation and protein damage induced by bile acids [14, 33, 53–55].

Additionally, in response to bile acid entry into the circulation, lipoprotein X emerges – a characteristic feature of cholestatic dyslipidemia. Lipoprotein X is considered an abnormal variant of low-density lipoprotein. It is primarily composed of non-esterified cholesterol (22%), phospholipids (66%), and albumin (6%), which form its structural core, along with minor amounts of triglycerides, cholesterol esters, and bile acids. Unlike conventional lipoproteins, Lp-X lacks a micellar structure; under electron microscopy, it appears as lamellar, multilayered vesicles with a diameter of 30–70 nm, often forming roll-like aggregates [56, 57]. It contains small amounts of apolipoproteins E and C, but notably lacks apolipoprotein B (ApoB). Apolipoprotein B serves as a ligand for LDL receptors; therefore, despite its compositional similarities to LDL, Lp-X is not taken up by LDL receptors in the liver. As a result, it fails to suppress hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity, allowing endogenous cholesterol synthesis to continue despite elevated serum cholesterol levels [33, 58]. The absence of ApoB in Lp-X may reflect a compensatory mechanism in cholestasis, facilitating the removal of excess cholesterol and bile acids via peripheral circulation, bypassing the dysfunctional liver. Consequently, total cholesterol levels in PBC increase not only due to impaired metabolism but also due to the accumulation of Lp-X, which has a density similar to that of LDL and is not distinguished from it in standard lipid assays [59]. Increase in cholesterol synthesis and Lp-X formation are thought to serve an adaptive function by binding bile acids, thereby helping to neutralize their detergent toxicity and facilitate their clearance from plasma [60]. Lp-X is not unique to PBC; it also appears in other forms of intrahepatic and extrahepatic cholestasis, as well as in conditions such as lecithin-cholesterol acyltransferase (LCAT) deficiency and following intravenous lipid administration. The precise mechanism and site of Lp-X formation are not fully understood, but it is hypothesized to originate extracellularly within the bile canaliculi, involving the canalicular phosphatidylcholine transporter Mdr2 P-glycoprotein [61, 62]. Bile-derived lipoprotein regurgitation into the systemic circulation is thought to play a central role in Lp-X formation. In vitro studies have shown that bile lipoproteins incubated with serum or albumin transform into Lp-X–like structures, while Lp-X incubated with bile acids reverts to a bile-type lipoprotein structure. The maintenance of Lp-X structure requires a specific albumin-to-bile acid ratio [63]. It is further suggested that in PBC, free bile acids entering the bloodstream – when not adequately bound to lipoproteins – may interact with phospholipids and cholesterol to form Lp-X, thereby neutralizing their detergent-like properties. This process appears to involve increased synthesis of phospholipids (from fatty acids) and free cholesterol, a pattern observed in patients with cholestasis. Additionally, redistribution of bile acids among different lipoproteins may occur, as suggested by the observed rapid decline in bile acid content in Lp-X—from 1 to 3% (as seen in bile lipoproteins) to < 0.01% [64]. The catabolism of Lp-X is thought to occur in the kidneys and the reticuloendothelial system, particularly the spleen, although the exact mechanisms remain poorly defined [59]. Accumulation of Lp-X in the kidneys has been associated with chronic glomerulopathy [65]. Moreover, Lp-X can contribute to hyperviscosity syndrome, which may present with hyponatremia and severe thromboembolic complications, including central retinal vein thrombosis and subsequent vision loss [66, 67].

Xanthomas

Dyslipidemia, particularly marked by elevated total cholesterol levels (often > 1000 mg/dL) and the presence of Lp-X, is associated with the development of xanthomas, also referred to as xanthelasma. These manifest as single or multiple light-yellow, nodular lesions [68]. They are most commonly located on the eyelids, but may also appear on the palms and pressure-prone areas such as the elbows, knees, and buttocks, and, in rare cases, in internal organs such as the stomach. Histologically, xanthomas are composed of foam cells – lipid-laden macrophages that accumulate within the dermis or submucosa [69, 70]. These lesions occur in fewer than 10% of patients with PBC and typically regress following the resolution of hyperlipidemia or after liver transplantation [33, 66].

Cardiovascular risk

Current research does not indicate that the dyslipidemia associated with PBC increases cardiovascular risk. In a study involving 930 patients with PBC, no elevated risk of myocardial infarction, stroke, or transient ischemic attack (TIA) was observed in this population [36]. Additionally, subclinical atherosclerosis was assessed in patients with PBC using ultrasound measurement of carotid intima-media thickness (IMT), and no association was found between PBC-related hypercholesterolemia and subclinical atherosclerosis [71]. A meta-analysis conducted by Liang et al. (2024) also demonstrated no significant difference in the prevalence of coronary artery disease between individuals with and without PBC and no increased risk of stroke and heart failure [72]. Similarly, the meta-analysis by Yun-Lu et al. (2024) concluded that PBC is not associated with an increased risk of coronary atherosclerosis; however, it reported associations between PBC and type 1 diabetes, type 2 diabetes, myocardial infarction, heart failure, hypertension, atrial fibrillation, stroke, ischemic stroke, and small-vessel ischemic stroke [73]. The clinical significance and underlying mechanisms of these associations require further clarification.

One proposed explanation for this phenomenon is the significantly elevated serum adiponectin levels observed in patients with PBC compared to individuals with hyperlipidemia in the absence of cholestasis. Adiponectin is a well-established cardioprotective factor [74]. In addition, the role of HDL concentration as a predictive marker for atherosclerotic complications has been emphasized. Apolipoprotein A1, the principal protein component of HDL, promotes cholesterol efflux from adipocytes and inhibits its accumulation in the vascular wall, thereby attenuating atherogenesis. HDL also induces the expression of lipocalin mRNA in partially differentiated adipocytes, increasing circulating lipocalin levels. Lipocalins modulate macrophage activity and prevent their transformation into foam cells, further inhibiting the development of atherosclerotic lesions [49].

Moreover, Lp-X itself may exert anti-atherosclerotic effects in PBC by preventing LDL oxidation and contributing to endothelial homeostasis. Due to their large size – approximately three times that of LDL particles – Lp-X lipoproteins are unable to penetrate the arterial wall, thereby reducing the risk of plaque formation [75].

Nonetheless, an increased cardiovascular risk has been noted in patients with coexisting PBC and metabolic syndrome, or in the presence of other independent cardiovascular risk factors [76]. This is of particular importance, as metabolic syndrome has been reported to occur in up to 30% of patients with PBC [77].

Bioactive lipids

Recent advances in lipidomics have significantly broadened our understanding of bioactive lipids, revealing the intricate complexity of the lipidome and its diverse biological functions. Unlike structural or energetic lipids, bioactive lipids are characterized by their responsiveness to specific stimuli and their ability to modulate distinct signaling cascades [78].

Accumulating evidence implicates these molecules in the pathogenesis of chronic liver diseases, particularly in processes such as inflammation, apoptosis, and fibrogenesis [79, 80]. Despite this, data on the role of bioactive lipids in cholestatic liver diseases, including PBC, remain limited [81]. Our own studies have identified dysregulations in several lipid classes—namely, acylcarnitines, free fatty acids, and sphingolipids – that appear to be associated with inflammatory and fibrotic responses [82, 83]. Notably, alterations involving derivatives of long-chain oleic acid (C18:1) were especially pronounced, suggesting a potential link between these lipid species and the pathophysiological mechanisms underlying PBC. High levels of free fatty acids, including oleic acid, in the blood of patients with PBC may have multiple potential causes, including impaired β-oxidation. This is particularly important in the context of the emergence of new drugs for PBC–PPAR agonists – which are key regulators of the β-oxidation process. In addition, as an adaptive response to circulating bile acids, enhanced synthesis of biliary phospholipids, rich in fatty acids such as oleic and palmitic acids, may increase the production and systemic appearance of these fatty acids, supporting bile acid neutralization and facilitating their clearance [60].

Bile acid-activated nuclear receptors

Lipidomic alterations observed in PBC are not merely the result of impaired bile secretion but also reflect complex dysregulation of nuclear and membrane-bound receptor signaling pathways that regulate lipid homeostasis, bile acid metabolism, and inflammatory responses. Among these, the farnesoid X receptor and peroxisome proliferator-activated receptors (PPARs) play particularly pivotal roles.

FXR plays a key role in maintaining bile acid homeostasis and broader metabolic regulation. Initially identified in 1995 as a nuclear hormone orphan receptor predominantly expressed in the liver, kidney, and adrenal glands, FXR was subsequently recognized as a key bile acid sensor following the discovery of bile acids as its endogenous ligands in 1999 [84, 85]. FXR regulates a range of genes central to bile acid synthesis, secretion, and enterohepatic recirculation. In particular, FXR-mediated repression of CYP7A1, the gene encoding cholesterol 7α-hydroxylase – the rate-limiting enzyme in bile acid synthesis – serves as a classic feedback mechanism. Through these pathways, FXR maintains the balance of the bile acid pool in coordination with the gut microbiota, which transforms primary bile acids into secondary forms, reinforcing the relevance of the gut-liver axis [86]. In cholestatic liver diseases such as PBC, elevated intrahepatic bile acid levels lead to sustained FXR activation. While this serves an adaptive function by downregulating bile acid synthesis, chronic FXR stimulation in PBC may have broader metabolic consequences. Beyond its standard roles, FXR influences lipid metabolism by modulating genes involved in lipogenesis, triglyceride turnover, and lipoprotein assembly. FXR activation is generally associated with reduced hepatic triglyceride accumulation and enhanced low-density lipoprotein metabolism. However, in the setting of chronic cholestasis, these regulatory pathways may become dysregulated, contributing to the characteristic paradoxical lipid profile seen in PBC. These findings underscore the complex and context-dependent role of FXR in PBC pathophysiology and raise questions regarding the long-term metabolic consequences of persistent FXR signaling in this population [87, 88].

PPARs are a family of nuclear hormone receptors first identified and cloned in 1990, recognized for their central role in regulating gene transcription linked to metabolic processes, inflammation, and carcinogenesis [89]. In hepatocytes, PPAR-α functions as a transcriptional regulator coordinating key processes such as β-oxidation of fatty acids, glucose production, lipid transport, and bile acid homeostasis, particularly during fasting – feeding transitions [90]. In the context of PBC, decreased PPAR-α activity has been implicated in impaired lipid clearance and enhanced hepatic inflammation, suggesting its potential role in the progression of cholestatic injury. Pharmacological activation of PPARs, particularly through fibrates such as bezafibrate and fenofibrate, has demonstrated clinical promise in PBC. These agents enhance bile flow, reduce cholestatic markers, and improve biochemical responses in patients with incomplete response to ursodeoxycholic acid. Furthermore, newer non-fibrate PPAR agonists, including seladelpar and elafibranor, are currently under investigation and show potential not only in modulating bile acid metabolism but also in addressing the inflammatory and metabolic dysregulation characteristic of PBC [91].

Treatment of dyslipidemia

The treatment of lipid disturbances in the context of PBC remains controversial, primarily due to concerns about the hepatotoxicity of hypolipidemic agents and the ambiguous cardiovascular risk associated with PBC-related dyslipidemia.

As Reshetnyak et al. concluded in their review (2022), lipid profile changes in PBC may serve a compensatory function aimed at neutralizing the detergent toxicity of bile acids that accumulate in the systemic circulation during cholestasis. In this context, the emergence of Lp-X, a biliary-type particle composed largely of cholesterol and phospholipids and thought to associate with bile acids, can be viewed as an adaptive mechanism that helps buffer bile acid cytotoxicity and support their elimination. Therefore, elevated total cholesterol in PBC, particularly when driven by Lp-X, should not by itself prompt lipid-lowering therapy; treatment decisions should be individualized and guided by standard cardiovascular indications and overall CVD risk, recognizing that total cholesterol may be misleading in Lp-X - predominant dyslipidemia and that excessive lipid suppression has been hypothesized to reduce the lipid capacity available for bile acid neutralization [60].

These uncertainties likely underlie the cautious recommendations from both the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD), which do not advocate for the routine use of lipid-lowering therapy in PBC. However, such treatments should be considered in patients with coexisting metabolic syndrome or other established cardiovascular risk factors, such as diabetes or primary hypercholesterolemia [31, 92].

It is recommended that all patients with PBC undergo assessment for traditional cardiovascular risk factors – including smoking, diabetes, hypertension, and body mass index (BMI) – in addition to a comprehensive lipid panel that includes apolipoprotein B. This is particularly important because standard LDL measurements do not distinguish between LDL and Lp-X, whereas apolipoprotein B is absent in Lp-X and correlates linearly with true LDL levels [93].

Statins, which inhibit HMG-CoA reductase, have been shown to be both effective and safe for the treatment of dyslipidemia in PBC, even in the presence of elevated liver enzyme levels. In one study, patients with PBC receiving 40 mg of simvastatin daily experienced a 34% reduction in total cholesterol within 30 days [94]. Furthermore, a recently published meta-analysis suggested that statin use in patients with chronic liver diseases may slow disease progression and reduce the risk of decompensation and mortality [95]. Nevertheless, given that statins are excreted in bile, caution is warranted in cases of significant cholestasis, as accumulation may lead to hepatotoxicity [96]. Additional caution is advised when prescribing statins to patients with decompensated cirrhosis [95].

Fibrates are another safe and effective treatment option for dyslipidemia in PBC. These agents lower total cholesterol, triglycerides, and non-HDL cholesterol levels [97]. Their hypolipidemic and anti-cholestatic effects are mediated via activation of PPARs, along with modulation of bile acid synthesis and secretion, making them particularly valuable in PBC management [98]. In one study assessing the efficacy of combining ursodeoxycholic acid with fenofibrate or bezafibrate, both combinations resulted in reduced alkaline phosphatase (ALP) activity and LDL cholesterol levels after 48 weeks, with the effect being more pronounced in the fenofibrate group [12].

Ursodeoxycholic acid is a secondary, hydrophilic bile acid found in the bile of humans and other mammals. It exerts multiple beneficial effects in cholestatic liver diseases, including immunomodulatory, choleretic, cytoprotective, and anti-apoptotic actions on hepatocytes and cholangiocytes. Although UDCA enhances cholesterol absorption in the gastrointestinal tract, its administration is associated with decreased total cholesterol and LDL levels, without affecting HDL or triglyceride concentrations [99].

Obeticholic acid, a semi-synthetic derivative of chenodeoxycholic acid, is a selective and potent agonist of farnesoid X receptors in hepatocytes and enterocytes, with approximately 100 times greater potency than endogenous bile acids. It enhances FGF-19 production, thereby reducing bile acid synthesis, and promotes bile secretion through upregulation of the bile salt export pump (BSEP). However, its effect on the lipid profile in PBC may be unfavorable, as it has been associated with reductions in HDL and total cholesterol levels and elevations in LDL levels [100, 101].

Plasmapheresis has been used in the treatment of hyperviscosity syndrome associated with Lp-X and its complications, although data on its efficacy are limited [56]. Statins, which act by increasing LDL receptor expression, are ineffective in managing Lp-X-related hypercholesterolemia, as Lp-X is not recognized or cleared by hepatic LDL receptors [96].

Conclusions

PBC is accompanied by a characteristic disturbance of lipid homeostasis driven by chronic cholestasis and FXR/FGF19-mediated adaptive downregulation of de novo bile acid synthesis, despite impaired enterohepatic circulation. Reduced biliary excretion of cholesterol and bile acids, altered enterohepatic signaling and impaired hepatic lipoprotein handling, together shape the PBC lipid phenotype. Clinically, this profile is defined by hypercholesterolemia, paradoxically elevated HDL in earlier stages, relatively modest triglyceride changes, and the appearance of lipoprotein X, which can dominate measured “LDL” and confound routine lipid interpretation. Available evidence suggests that PBC-related dyslipidemia does not translate into a uniformly increased risk of atherosclerotic cardiovascular disease. However, cardiovascular risk is not negligible in patients with coexisting metabolic syndrome or traditional risk factors, and risk assessment should follow standard preventive frameworks. In this setting, apolipoprotein B measurement is particularly useful to estimate “true” atherogenic particle burden, given the absence of ApoB in LpX. Beyond conventional lipoproteins, lipidomics indicates that bioactive lipid classes (e.g., sphingolipids and acylcarnitines) may reflect or contribute to hepatic inflammation, mitochondrial stress, and fibrogenesis in PBC. These findings support integrating targeted lipidomic profiling into pathophysiology-focused studies and biomarker development, particularly for disease stratification, assessment of treatment response, and prediction of progression. Future work should prioritize longitudinal, stage-stratified studies to clarify the determinants and consequences of Lp-X formation and clearance and to refine personalized treatment algorithms that address cholestasis, inflammation, and systemic metabolic risk.

Abbreviations

AASLD

American Association for the Study of Liver Diseases

ALP

Alkaline phosphatase

AMA-M2

antimitochondrial antibodies, M2 subtype

ApoB

Apolipoprotein B

BMI

Body mass index

BSEP

Bile salt export pump

CYP7A1

Cholesterol 7α–hydroxylase

EASL

European Association for the Study of the Liver

FGF

Fibroblast growth factor

FGFR

Fibroblast growth factor receptor

FXR

Farnesoid X receptor

HDL

High–density lipoprotein

HMG-CoA

3–hydroxy–3–methylglutaryl coenzyme A

IFN-γ

interferon gamma

IL-17

interleukin 17

IMT

Intima–media thickness

LCAT

Lecithin–cholesterol acyltransferase

LDL

Low–density lipoprotein

Lp-X

lipoprotein X

Mdr2

Multidrug resistance protein 2

PBC

Primary biliary cholangitis

PDC-E2

pyruvate dehydrogenase complex, E2 subunit

PPAR

Peroxisome proliferator–activated receptor

TC

Total cholesterol

TG

Triglycerides

TIA

Transient ischemic attack

UDCA

Ursodeoxycholic acid

VLDL

Very low–density lipoprotein

Authors’ contributions

Conceptualization - M.R.; writing—original draft preparation - M.R.; writing—review and editing - M.R., P.R., A.B.-Z., A.A., P.Z. and R.F.; visualization, M.R. and A.A.;All authors have read and agreed to the published version of the manuscript.

Funding

This article received no external funding.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.