Farnesoid X receptor (FXR) is a key regulator of bile acid, lipid, and glucose homeostasis, making it a promising target for treating metabolic diseases. FXR antagonists have shown therapeutic potential in cholestasis, metabolic disorders, and certain cancers, while clinically approved FXR antagonists remain unavailable and underrepresented in current treatment strategies. To address this, we developed deep learning models for predicting FXR antagonistic activity (ANTCL) and toxicity (TOXCL). Screening 217,345 compounds from the HMDB database identified eleven human metabolite candidates with significant FXR binding potential. Molecular dynamics simulations and binding free energy calculations revealed five more stable complexes compared to the reference compound Gly-MCA, with HMDB0253354 (Fulvestrant) and HMDB0242367 (ZM 189154) standing out for their binding free energies. Hydrophobic interactions, particularly involving residues MET328, PHE329, and ALA291, contributed to their stability. These results demonstrate the effectiveness of deep learning in FXR antagonist discovery and highlight the potential of HMDB0253354 and HMDB0242367 as promising candidates for metabolic disease treatment.

Knowledge of the etiological and pathogenetic mechanisms of the development of any disease is essential for its treatment. Because the cause of primary biliary cholangitis (PBC), a chronic, slowly progressive cholestatic liver disease, is still unknown, treatment remains symptomatic. Knowledge of the physicochemical properties of various bile acids and the adaptive responses of cholangiocytes and hepatocytes to them has provided an important basis for the development of relatively effective drugs based on hydrophilic bile acids that can potentially slow the progression of the disease. Advances in the use of hydrophilic bile acids for the treatment of PBC are also associated with the discovery of pathogenetic mechanisms of the development of cholangiocyte damage and the appearance of the first signs of this disease. For 35 years, ursodeoxycholic acid (UDCA) has been the unique drug of choice for the treatment of patients with PBC. In recent years, the list of hydrophilic bile acids used to treat cholestatic liver diseases, including PBC, has expanded. In addition to UDCA, the use of obeticholic acid, tauroursodeoxycholic acid and norursodeoxycholic acid as drugs is discussed. The pathogenetic rationale for treatment of PBC with various bile acid drugs is discussed in this review. Emphasis is made on the mechanisms explaining the beneficial therapeutic effects and potential of each of the bile acid as a drug, based on the understanding of the pathogenesis of the initial stages of PBC.

Drug-induced liver injury (DILI) is a global problem and can develop from exposure to prescription or over-the-counter medications as well as herbal and dietary supplements. The diagnosis of DILI is clinically challenging, and liver injury can be severe leading to liver failure, death, or liver transplantation. Patients with underlying chronic liver diseases (CLD) may be at increased risk for DILI, which is associated with factors related to drug or liver disease.

This review summarises current knowledge on the risk and outcomes of DILI in patients with CLD.

Patients with CLD may be at an increased risk for DILI. Additionally patients with underlying CLD are at risk for more severe liver injury and worse outcomes after DILI.

The risk for and poor outcomes from DILI are accentuated in patients with CLD and potentially leading to the worst-case scenario of acute-on-chronic liver failure. We highlight the key observations on DILI with a broad range of underlying liver diseases and the high-DILI risk agents implicated in those populations.

Swertia cincta is a traditional remedy for cholestasis commonly utilised in Yunnan, China. Despite its widespread use, the specific active components and underlying mechanisms of action remain poorly understood.

This study aimed to investigate the therapeutic properties, mechanisms, and active compounds of Swertia cincta in an animal model of cholestasis induced by alpha-naphthylisothiocyanate (ANIT).

UHPLC/Q-TOF-MS and high-performance liquid chromatography (HPLC) were utilised to analyse the blood components of Swertia cincta. An ANIT-induced cholestatic liver injury animal model was established, and metabolomics was employed to explore the potential mechanisms of Swertia cincta in treating cholestatic liver injury. Hepatocellular injury induced by taurochenodeoxycholic acid was evaluated in vitro, and key bioactive components of Swertia cincta for cholestatic liver injury treatment were identified and confirmed using the ANIT-induced mouse model.

The established HPLC method demonstrates good specificity and reproducibility, enabling the simultaneous determination of six components in Swertia cincta. Results from serum biochemical indicators and liver pathology analysis indicated that Swertia cincta exhibits promising anti-cholestasis liver injury effects. Specifically, gentiopicroside, loganic acid, and isoorientin were identified as key active ingredients in treating cholestatic liver injury. Their mechanism of action primarily involves regulating PPAR-α, FXR, CYP3A4, NTCP, CAR, and CPT2. By modulating PPAR-α and bile acid metabolism-related proteins, reducing pro-inflammatory factors, enhancing bile acid transport, and promoting fatty acid oxidation to reduce lipid accumulation, Swertia cincta exerts protective and therapeutic effects against cholestatic liver injury. Notably, gentian bitter glycosides appear to be the most critical components for this effect.

Swertia cincta may improve cholestatic liver injury by activating the peroxisome proliferator-activated receptor alpha pathway, and the key active compounds were gentiopicroside, loganic acid, and isoorientin.

Chronic hepatobiliary damage progressively leads to fibrosis, which may evolve into cirrhosis and/or hepatocellular carcinoma. The fight against the increasing incidence of liver-related morbidity and mortality is challenged by a lack of clinically validated early-stage biomarkers and the limited availability of effective anti-fibrotic therapies. Current research is focused on uncovering the pathogenetic mechanisms that drive liver fibrosis. Drugs targeting molecular pathways involved in chronic hepatobiliary diseases, such as inflammation, hepatic stellate cell activation and proliferation, and extracellular matrix production, are being developed. Etiology-specific treatments, such as those for hepatitis B and C viruses, are already in clinical use, and efforts to develop new, targeted therapies for other chronic hepatobiliary diseases are ongoing. In this review, we highlight the major molecular changes occurring in patients affected by metabolic dysfunction-associated steatotic liver disease, viral hepatitis (Delta virus), and autoimmune chronic liver diseases (autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis). Further, we describe how this knowledge is linked to current molecular therapies as well as ongoing preclinical and clinical research on novel targeting strategies, including nucleic acid-, mesenchymal stromal/stem cell-, and extracellular vesicle-based options. Much clinical development is obviously still missing, but the plethora of promising potential treatment strategies in chronic hepatobiliary diseases holds promise for a future reversal of the current increase in morbidity and mortality in this group of patients.

Saroglitazar magnesium, a dual PPAR α/γ agonist, currently in Phase III for treating primary biliary cholangitis (PBC), was evaluated for its pharmacokinetic (PK) profile, safety, and pharmacodynamics in participants with cholestatic liver disease (CLD) across different levels of hepatic impairment (HI) and participants with severe renal impairment (RI). Three PK studies comparing saroglitazar with healthy controls were conducted: Study 1 involved daily oral doses of 1 or 2 mg for 4 weeks in 12 PBC cirrhosis participants with mild or moderate HI; Study 2 assessed single-dose PK (2 or 4 mg) in eight non-cirrhotic CLD participants; Study 3 evaluated single-dose PK (2 mg) in eight participants with severe RI. On day 1, saroglitazar exposure increased by 14.6-42% in mild HI vs. normal, but by day 28, levels were similar, indicating no accumulation. In moderate HI, exposure was significantly increased by 50.4-85% on days 1 and 28, with 34-46% lower clearance despite a similar half-life. The moderate HI group had a 59% higher exposure than the non-cirrhotic group. Saroglitazar (1 and 2 mg) reduced alkaline phosphatase (ALP) levels by 17-40% after 4 weeks in participants with abnormal baseline ALP. Single-dose PK in non-cirrhotic CLD (2 and 4 mg) and severe RI (2 mg) was comparable to matched controls without significant safety issues. Overall, saroglitazar (1 and 2 mg) was safe and well-tolerated in cholestatic cirrhosis with mild HI and participants with severe RI without major PK changes. Moderate HI increased exposure and decreased clearance without any safety concerns.

Based on the Adverse Event Reporting System (FAERS) data from the US FDA, this study mined the adverse drug reactions of obeticholic acid (OCA) in the real world and provided reference for clinical safe drug use.

Adverse event reports for OCA from the second quarter of 2016 to the third quarter of 2023 were extracted. The analysis for adverse reaction signal detection was conducted using reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker methods.

A total of 5661 OCA-related adverse event reports were collected, and 105 OCA-related adverse reaction signals were obtained, involving 14 systems, among which 46 new signals were not previously mentioned in the product labeling. Severe adverse event of OCA accounted for a relatively high proportion (1445 cases, 25.53%), among which the number of hospitalization reports was the largest (1042 cases, 18.41%). The top five adverse events were pruritus, fatigue, constipation, elevated blood alkaline phosphatase, and abdominal distention. The top five adverse reaction signals intensity were abnormal blood alkaline phosphatase, abnormal ratio of albumin globulin, spider nevus, combined with abnormal bilirubin, and γ-abnormal glutamyl transferase.

Based on the pharmacovigilance study of the FAERS database, it is necessary to strengthen the clinical medication monitoring of OCA, so as to provide reference for effective pharmaceutical monitoring and rational clinical medication.

Geniposide (GE), a bioactive compound extracted from the fruit of Gardenia jasminoides Ellis, has attracted significant attention for its hepatoprotective therapeutic applications. Although GE displays a protective effect on treating intrahepatic cholestasis (IC), the underlying mechanism remains elusive. In this study, we aimed to elucidate the pharmacological mechanisms of GE in treating IC by an integrated analysis of transcriptomics and metabolomics. Firstly, we evaluated the hepatoprotective effect of GE in α-naphthylisothiocyanate (ANIT)-induced IC rats by examining biochemical indices, inflammatory factors, and oxidative stress levels. Secondly, by transcriptomics and serum metabolomics, we identified differentially expressed genes and metabolites, revealing phenotype-related metabolic pathways and gene functions. Lastly, we screened the core targets of GE in the treatment of IC by integrating transcriptomic and metabolomic data and validated these targets using western blotting. The results indicated that GE improved serum indexes and alleviated inflammation reactions and oxidative stress in the liver. The transcriptomics analysis revealed 739 differentially expressed genes after GE treatment, mainly enriched in retinol metabolism, steroid hormone synthesis, PPAR signal transduction, bile secretion metabolism, and other pathways. The metabolomics analysis identified 98 differential metabolites and 10 metabolic pathways. By constructing a "genes-targets-pathways-compounds" network, we identified two pathways: the bile secretion pathway and the glutathione pathway. Within these pathways, we discovered nine crucial targets that were subsequently validated through western blotting. The results revealed that the GE group significantly increased the expression of ABCG5, NCEH1, OAT3, and GST, compared with the ANIT group. We speculate that GE has a therapeutic effect on IC by modulating the bile secretion pathway and the glutathione pathway and regulating the expression of ABCG5, NCEH1, OAT3, and GST.

Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) are characterized by the destruction of the small bile ducts and the formation of multifocal biliary strictures, respectively, impairing bile flow. This leads to the hepatic accumulation of bile acids, causing liver injury and the risk of progression to cirrhosis and liver failure. First-line therapy for PBC is ursodeoxycholic acid, although up to 40% of treated individuals are incomplete responders, and there is no effective therapy for PSC, highlighting the need for better therapeutic options in these diseases. In addition, pruritus is a common symptom of cholestasis that has severe consequences for quality of life and is often undertreated or untreated. Nuclear receptors are pharmacological targets to treat cholestasis due to their multifactorial regulation of hepatic enzymatic pathways, particularly in bile acid metabolism. The peroxisome proliferator-activated receptor (PPAR) is of significant clinical interest due to its role in regulating bile acid synthesis and detoxification pathways. PPAR agonism by fibrates has traditionally been explored due to PPARα's expression in the liver; however, recent interest has expanded to focus on newer PPAR agonists that activate other PPAR isoforms, for example, δ, γ, alone or in combination. Several PPAR agonists have been investigated as second-line therapy for people living with PBC, including the recent accelerated United States Food and Drug Administration approval of elafibranor and seladelpar. This review evaluates available data on the efficacy and safety of the five PPAR agonists investigated for the treatment of cholestasis and associated pruritus in PBC and PSC, namely fenofibrate, bezafibrate, saroglitazar, elafibranor, and seladelpar.

Chronic itch is a debilitating symptom profoundly impacting the quality of life in patients with liver diseases like cholestasis. Activation of the human G-protein coupled receptor, MRGPRX4 (hX4), by bile acids (BAs) is implicated in promoting cholestasis itch. However, the detailed underlying mechanisms remain elusive. Here, we identified 3-sulfated BAs that are elevated in cholestatic patients with itch symptoms. We solved the cryo-EM structure of hX4-Gq in a complex with 3-phosphated deoxycholic acid (DCA-3P), a mimic of the endogenous 3-sulfated deoxycholic acid (DCA-3S). This structure revealed an unprecedented ligand-binding pocket in MRGPR family proteins, highlighting the crucial role of the 3-hydroxyl (3-OH) group on BAs in activating hX4. Guided by this structural information, we designed and developed compound 7 (C7), a BA derivative lacking the 3-OH. Notably, C7 effectively alleviates hepatic injury and fibrosis in liver disease models while significantly mitigating the itch side effects.

The characteristics of autoimmune liver diseases (AILDs), including primary biliary cholangitis (PBC), autoimmune hepatitis (AIH), and PBC-AIH overlap syndrome (OS), have rarely been investigated and compared in Asia.

At the Taiwan tertiary referral center, 330 PBC patients (87% treated with ursodeoxycholic acid [UDCA]), 143 AIH patients (94.4% treated with immunosuppressive therapy [IST]) and 21 PBC-AIH OS patients (85.7% treated with UDCA and IST) were enrolled.

Compared with AIH patients, PBC patients were older at baseline and had greater female-to-male sex ratios, alkaline phosphatase (ALP) and γ-glutamyl transferase (γ-GT) levels, and liver cirrhosis (LC), dyslipidemia, and hepatic and cardiometabolic complication rates. PBC patients had the lowest transaminase levels, whereas AIH patients had the highest transaminase levels. PBC patients had greater 22-year all-cause mortality and liver transplantation (ACMaLT) (43.5 vs 25.4%, P = 0.004), LC (75 vs 58.5%, P < 0.01), dyslipidemia (54.4 vs 45.9%, P = 0.001), and cerebrovascular accident (11.3 vs 0.8%, P = 0.019) cumulative incidences (CIs) than did AIH patients; PBC-AIH OS patients had greater systemic lupus erythematosus (28.9 vs 8.9%, P = 0.009) CI than did PBC patients. Baseline ALP (hazard ratio: 1.001), albumin (0.514), platelet count (0.997), and LC (3.438) were associated with ACMaLT; age (1.110), albumin (0.350), cirrhosis (46.219), and hepatitis C virus antibody positivity (5.068) were associated with hepatocellular carcinoma (HCC); and female sex (2.183) and body mass index (1.054) were associated with autoimmune diseases.

Compared with AIH patients, PBC patients had greater cardiometabolic CI, and ACMaLT CI, which was associated with cholestasis, liver functional reserve and LC. Older AILD patients with LC and females with obesity demand special caution for the development of HCC and extrahepatic autoimmune diseases, respectively.

Background/Objectives: Primary biliary cholangitis (PBC) is an autoimmune chronic cholestatic disease of the liver that symptomatically can present with pruritus and fatigue. Its established first- and second-line therapies are ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) although they provide limited symptom management. Liver transplantation offers a potentially curative therapeutic option in refractory cases progressing to cirrhosis. Novel research published after the current guidelines highlights the importance of providing an up-to-date analysis of treatment options available. Methods: In this study, we conducted a literature search using Pubmed, Ovid Medline, and SCOPUS to provide a narrative review of first-line, second-line, and emerging therapies in PBC. Results: UDCA has been well established as a long-term, safe therapy within the literature although it is possible that treatment dosage can be further optimised in refractory patients. It has a favourable side effect profile. Despite improving biochemical markers, histopathological profile, and overall outcomes, up to 30-40% of patients are refractory to it. Age and sex are highlighted as independent indicators of non-responsiveness. This necessitates effective second-line therapies. Future trials could aim to investigate UDCA as a co-first-line therapy. Further supporting results for OCA were found in the interim extension trial of the seminal POISE study. The long-term phase 4 COBOLT trial is still awaiting results to further assess the complications, adherence, and potential adverse effects. It is a viable option in UDCA-refractory patients. The high incidence rate of dose-related pruritis indicates that alternative second-line options are needed. Bezafibrate is an off-label antilipemic agent that shows promise as a prospective second-line therapy option. The landmark BEZURSO trial alleviated some efficacy and safety concerns, but it remains associated with elevated serum creatinine; thus, it should be considered with caution. Other prospective second-line therapies are budesonide, triple therapy, and novel agents such as seladelpar and elafibranor. Conclusions: UDCA should remain the treatment of choice for PBC, though perhaps not as monotherapy. With further investigation, BF shows promise as a new second-line therapy alongside OCA, which it may outperform.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The management landscape was transformed 20 years ago with the advent of ursodeoxycholic acid. Up to 40% of patients do not, however, respond adequately to ursodeoxycholic acid and therefore still remain at risk of disease progression to cirrhosis. The introduction of obeticholic acid as a second-line therapy for patients failing ursodeoxycholic acid has improved outcomes for patients with PBC. There remains, however, a need for better treatment for patients at higher risk. The greatest threat facing our efforts to improve treatment in PBC is, paradoxically, the regulatory approval model providing conditional marketing authorization for new drugs based on biochemical markers on the condition that long-term, randomized placebo-controlled outcome trials are performed to confirm efficacy. As demonstrated by the COBALT confirmatory study with obeticholic acid, it is difficult to retain patients in the required follow-on confirmatory placebo-controlled PBC outcome trials when a licensed drug is commercially available. New PBC therapies in development, such as the peroxisome proliferator-activated receptor agonists, face even greater challenges in demonstrating outcome benefit through randomized placebo-controlled studies once following conditional marketing authorization, as there will be even more treatment options available. A recently published EMA Reflection Paper provides some guidance on the regulatory pathway to full approval but fails to recognize the importance of real-world data in providing evidence of outcome benefit in rare diseases. Here we explore the impact of the EMA reflection paper on PBC therapy and offer pragmatic solutions for generating evidence of long-term outcomes through real-world data collection.

The objective of this study was to compare the safety profiles of OCA and UDCA for the treatment of PBC using the FDA Adverse Event Reporting System database.

We extracted reports for OCA from 2016 to 2023 and UDCA from 2004 to 2023. Demographic details, adverse events (AEs), and concomitant medications were analyzed using descriptive statistics and signal detection methods.

The most common for OCA were pruritus (1345 cases, ROR 20.96) and fatigue (528 cases, ROR 3.46). UDCA was more frequently associated with hepatocellular carcinoma (22 cases, ROR 16.37) and type I hypersensitivity reactions (11 cases, ROR 12.77). OCA was also linked to a higher frequency of constipation (161 cases, ROR 3.92) and increased blood alkaline phosphatase levels (145 cases, ROR 44.27).

This study reveals distinct safety profiles for OCA and UDCA in the treatment of PBC. OCA is associated with a higher frequency of pruritus, fatigue, constipation, and increased blood alkaline phosphatase levels, while UDCA is linked to hepatocellular carcinoma and type I hypersensitivity reactions. These findings support personalized treatment approaches based on individual patient characteristics.

Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.

Patient-reported outcomes (PROs), such as health-related quality of life (HRQL), are important outcome measures for patients with chronic liver diseases (CLDs). Presence of cirrhosis and advanced liver disease have been associated with worsened HRQL and fatigue. On the other hand, some patients with earlier stages of CLD also experience fatigue, causing PRO impairment. Treatment for some CLDs may improve HRQL and, sometimes, levels of fatigue. We aimed to provide an in-depth expert review of concepts related to fatigue and HRQL in patients with primary biliary cholangitis, hepatitis C virus and MASLD (metabolic dysfunction-associated steatotic liver disease). A panel of experts in fatigue and CLD reviewed and discussed the literature and collaborated to provide this expert review of fatigue in CLD. Herein, we review and report on the complexity of fatigue, highlighting that it is comprised of peripheral (neuromuscular failure, often in conjunction with submaximal cardiorespiratory function) and central (central nervous system dysfunction) causes. Fatigue and HRQL are measured using validated self-report instruments. Additionally, fatigue can be measured through objective tests (e.g. grip strength). Fatigue has deleterious effects on HRQL and one's ability to be physically active and socially engaged but does not always correlate with CLD severity. Treatments for hepatitis C virus and MASLD can improve levels of fatigue and HRQL, but current treatments for primary biliary cholangitis do not seem to affect levels of fatigue. We conclude that obtaining PRO data, including on HRQL and fatigue, is essential for determining the comprehensive burden of CLD and its potential treatments.

Cholestasis is a chronic liver disease with limited therapeutic options. Hydrophobic bile acid-induced hepatobiliary injury is a major pathological driver of cholestasis progression. This study investigates the anti-cholestasis efficacy and mechanisms of action of glycine-conjugated β-muricholic acid (Gly-β-MCA). We use female Cyp2c70 KO mice, a rodent cholestasis model that does not produce endogenous muricholic acid (MCA) and exhibits a "human-like" hydrophobic bile acid pool and female-dominant progressive hepatobiliary injury and portal fibrosis. The efficacy of Gly-β-MCA and ursodeoxycholic acid (UDCA), the first line drug for cholestasis, on cholangiopathy and portal fibrosis are compared. At a clinically relevant dose, Gly-β-MCA shows comparable efficacy as UDCA in reducing serum transaminase, portal inflammation and ductular reaction, and better efficacy than UDCA against portal fibrosis. Unlike endogenous bile acids, orally administered Gly-β-MCA is absorbed at low efficiency in the gut and enters the enterohepatic circulation mainly after microbiome-mediated deconjugation, which leads to taurine-conjugated MCA enrichment in bile that alters enterohepatic bile acid pool composition and reduces bile acid pool hydrophobicity. Gly-β-MCA also promotes fecal excretion of endogenous hydrophobic bile acids and decreases total bile acid pool size, while UDCA treatment does not alter total bile acid pool. Furthermore, Gly-β-MCA treatment leads to gut unconjugated MCA enrichment and reduces gut hydrophobic lithocholic acid (LCA) exposure. In contrast, UDCA treatment drives a marked increase of LCA flux through the large intestine. In conclusion, Gly-β-MCA is a potent anti-cholestasis agent with potential clinical application in treating human cholestasis.

Background. Obeticholic acid (OCA) has emerged as a promising drug in the management of nonalcoholic fatty liver disease (NAFLD). This meta-analysis aimed to analyse the therapeutic effect of OCA on NAFLD. Methods. Randomized controlled trials (RCTs) involving patients with NAFLD receiving OCA in the intervention arm and placebo in the control arm were searched throughout the electronic databases. The primary outcomes were changes in non-invasive markers of hepatic fibrosis and liver histology. The secondary outcomes included changes in liver enzymes, metabolic parameters from baseline and adverse events (AEs). Results. Four RCTs involving 1,278 subjects met the inclusion criteria. Over 6 weeks to 18 months of clinical use, OCA outperformed placebo in resolving definite nonalcoholic steatohepatitis (odds ratio [OR] 1.60, 95% confidence interval [CI] [1.04-2.48], p=0.03) and improving fibrosis (OR 2.23, 95% CI [1.56-3.20], p<0.0001), hepatocellular ballooning (OR 1.83, 95% CI [1.35-2.47], p<0.0001) and lobular inflammation (OR 1.62, 95% CI [1.13-2.32], p=0.009). OCA did not improve the enhanced liver fibrosis score and steatosis better than placebo, and demonstrated superior efficacy compared with the placebo in reducing serum alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase levels. Although a favourable effect of OCA over placebo was seen in body-weight reduction, the OCA use was associated with adverse changes in lipid parameters. Except for the greater risk of pruritus and constipation, the AE profile was comparable between the OCA and placebo groups. Conclusions. OCA has a favourable efficacy in improving liver histology and liver enzymes. However, the worsening of lipid parameters and other AEs with the OCA use warrants further investigation.

Bile acids serve as endogenous ligands for nuclear and cell membrane receptors and play a crucial role in bile acid and lipid metabolism. These detergent-like compounds promote bile flow and aid in the absorption of dietary fats and fat-soluble vitamins in the intestine. Synthesized in the liver as end products of cholesterol catabolism, bile acids exhibit a chemical structure comprising a nucleus and a side chain featuring a carboxyl group, with diverse steric arrangements and potential polar substituents. Critical interactions occur between bile acid species and various nuclear and cell membrane receptors, including the farnesoid X receptor and G-protein-coupled bile acid receptor 1. This research aimed to review the literature on bile acids and their roles in treating different diseases. Currently, numerous investigations are concentrating on specific bile acid species that target nuclear receptors in the gastrointestinal system, aiming to improve the treatment of conditions such as nonalcoholic fatty liver disease. Given the global attention this topic has garnered from research groups, it is considered relatively new, thus anticipating some gaps or incomplete data. Bile acid species have a significant therapeutic promise, especially in their ability to activate or inhibit nuclear receptors, such as farnesoid X receptor. This research provides to offer essential information for scientists and medical practitioners interested in discovering new studies that underscore the importance of bile acids in ameliorating and impeding the progression of disorders. Furthermore, it opens avenues for previously overlooked bile acid-based therapies.

The gut microbiota is widely regarded as a "metabolic organ" that could generate myriad metabolites to regulate human metabolism. As the microbiota metabolites, bile acids (BAs) have recently been identified as the critical endocrine molecules that mediate the cross-talk between the host and intestinal microbiota. This study provided a comprehensive insight into the gut microbiota and BA research through bibliometric analysis from 2003 to 2022. The publications on this subject showed a dramatic upward trend. Although the USA and China have produced the most publications, the USA plays a dominant role in this expanding field. Specifically, the University of Copenhagen was the most productive institution. Key research hotspots are the gut-liver axis, short-chain fatty acids (SCFAs), cardiovascular disease (CVD), colorectal cancer (CRC), and the farnesoid x receptor (FXR). The molecular mechanisms and potential applications of the gut microbiota and BAs in cardiometabolic disorders and gastrointestinal cancers have significant potential for further research.

Primary sclerosing cholangitis (PSC) is a challenging cholestatic liver disease marked by progressive bile duct inflammation and fibrosis that has no FDA-approved therapy. Although obeticholic acid (OCA) has been sanctioned for PSC, its clinical utility in PSC is constrained by its potential hepatotoxicity. Here, we introduce a novel therapeutic construct consisting of OCA encapsulated within a reactive oxygen species (ROS)-responsive, biodegradable polymer, further cloaked with human placenta-derived mesenchymal stem cell (hP-MSC) membrane (MPPFTU@OCA). Using PSC patient-derived organoid models, we assessed its cellular uptake and cytotoxicity. Moreover, using a PSC mouse model induced by 3,5-diethoxycarbonyl-1,4-dihydro-collidine (DDC), we demonstrated that intravenous administration of MPPFTU@OCA not only improved cholestasis via the FXR-SHP pathway but also reduced macrophage infiltration and the accumulation of intracellular ROS, and alleviated mitochondria-induced apoptosis. Finally, we verified the ability of MPPFTU@OCA to inhibit mitochondrial ROS thereby alleviating apoptosis by measuring the mitochondrial adenosine triphosphate (ATP) concentration, ROS levels, and membrane potential (ΔΨm) using H2O2-stimulated PSC-derived organoids. These results illuminate the synergistic benefits of integrating an ROS-responsive biomimetic platform with OCA, offering a promising therapeutic avenue for PSC.

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic disease characterized by the destruction of the small intrahepatic bile ducts, which can progress to liver cirrhosis. The gold standard in the treatment of PBC is ursodeoxycholic acid (UDCA), which is indicated in all patients with PBC because it improves not only biochemical parameters but also patients' survival. An important milestone in the identification of patients at risk is the assessment of biochemical response to UDCA. Patients who respond to treatment have a lower incidence of hepatic events and better prognosis than patients who do not. Several scoring systems can be used to assess the response and identify non-responders who will benefit from second-line treatment. Obeticholic acid (OCA) is currently the only approved second-line treatment for PBC, which is effective for non-responders to UDCA therapy or patients, who have not tolerated UDCA therapy. However, OCA is contraindicated in advanced liver cirrhosis and portal hypertension. Moreover, pruritus may be a limiting factor for the administration of OCA. Fibrates have shown promising data supporting their use in non-responders to UDCA because they improve the biochemical parameters and elastographic findings and have possible antipruritic effects. Therefore, the idea of a triple treatment seems interesting. Clinical research is focusing on several other groups of drugs: peroxisome proliferator-activated receptor (PPAR) δ- and α/δ agonists, non-steroidal farnesoid X receptor agonists, fibroblast growth factor 19 modulators, and inhibitors of nicotinamide adenine dinucleotide phosphate oxidase 1 and 4.

The Farnesoid X receptor (FXR) is a key transcription factor that is involved in the bile acid signaling network. The modulation of the FXR activity influences glucose and lipid homeostasis, reduces obesity and insulin resistance, as well as it regulates the pathogenesis of inflammatory and metabolic disorders. FXR ligands have therefore emerged in drug discovery as promising therapeutic agents for the prevention and treatment of gastrointestinal and liver diseases, including cancer.

Recent advances in the field of FXR modulators are reviewed, with a particular attention on patent applications filed in the past 5 years related to both the discovery and development of FXR targeting drugs.

FXR agonists have proven their efficacy and safety in humans and have shown a significant potential as clinical agents to treat metabolic and inflammatory associated conditions. However, several challenges, including adverse events such as pruritus, remain to be solved. Current studies aim to gain insights into the pathophysiological mechanisms by which FXR regulates metabolism and inflammation in terms of tissue/organ/isoform-specificity, post-translational modifications and coregulatory proteins, on the route of novel, improved FXR modulators.

Drug repurposing involves the investigation of existing drugs for new indications. It offers a great opportunity to quickly identify a new drug candidate at a lower cost than novel discovery and development. Despite the importance and potential role of drug repurposing, there is no specific definition that healthcare providers and the World Health Organization credit. Unfortunately, many similar and interchangeable concepts are being used in the literature, making it difficult to collect and analyze uniform data on repurposed drugs. This research was conducted based on understanding general criteria for drug repurposing, concentrating on liver diseases. Many drugs have been investigated for their effect on liver diseases even though they were originally approved (or on their way to being approved) for other diseases. Some of the hypotheses for drug repurposing were first captured from the literature and then processed further to test the hypothesis. Recently, with the revolution in bioinformatics techniques, scientists have started to use drug libraries and computer systems that can analyze hundreds of drugs to give a short list of candidates to be analyzed pharmacologically. However, this study revealed that drug repurposing is a potential aid that may help deal with liver diseases. It provides available or under-investigated drugs that could help treat hepatitis, liver cirrhosis, Wilson disease, liver cancer, and fatty liver. However, many further studies are needed to ensure the efficacy of these drugs on a large scale.

Up to 40% of Primary biliary cholangitis (PBC) patients have a suboptimal response to Ursodeoxycholic acid (UDCA). Close to half of such patients show a remarkable improvement when additionally treated with Obeticholic acid (OCA) but have a dose-dependent increase of pruritus. This relative success of OCA, a first-in-class Farnesoid receptor (FXR) agonist, has positioned FXR as an attractive target for drug development. Novel candidates have since emerged, providing hope for this subgroup of patients who lack effective and safe treatments.

We discussed the role of bile acids in PBC pathogenesis and how the FXR agonists provide therapeutic value by affecting bile acid synthesis and transport. Novel FXR agonists undergoing pre-clinical and clinical trials for PBC were enlisted via literature search by including the terms 'FXR agonists,' 'FXR PBC,' 'PBC clinical trials' on PubMed, MEDLINE via Ovid, and Clinicaltrials.gov.

Novel FXR agonists currently under investigation for PBC improve the disease surrogate markers in early trials. However, as with OCA, pruritus remains a concern with the newer drugs despite targeted chemical modifications to increase FXR specificity. Directing future resources toward studying the molecular mechanisms behind pruritus may lead to better drug design and efficacious yet safer drugs.

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver disorders of varying severity, ultimately leading to fibrosis. This spectrum primarily consists of NAFL and non-alcoholic steatohepatitis. The pathogenesis of NAFLD is closely associated with disturbances in the gut microbiota and impairment of the intestinal barrier. Non-gut commensal flora, particularly bacteria, play a pivotal role in the progression of NAFLD. Notably, Porphyromonas gingivalis, a principal bacterium involved in periodontitis, is known to facilitate lipid accumulation, augment immune responses, and induce insulin resistance, thereby exacerbating fibrosis in cases of periodontitis-associated NAFLD. The influence of oral microbiota on NAFLD via the "oral-gut-liver" axis is gaining recognition, offering a novel perspective for NAFLD management through microbial imbalance correction. This review endeavors to encapsulate the intricate roles of oral bacteria in NAFLD and explore underlying mechanisms, emphasizing microbial control strategies as a viable therapeutic avenue for NAFLD.

In assessing individual cardiovascular risk, dyslipidemia is known for emerging as a pivotal factor significantly contributing to major cardiovascular events. However, dyslipidemic patients frequently present with concurrent medical conditions, each with varying frequencies of occurrence; cholangitis, whether acute or chronic, and hepatic steatosis, along with associated conditions, are strongly associated with specific forms of dyslipidemia, and these associations are reasonably well elucidated. Conversely, evidence linking biliary disease to hepatic steatosis is comparatively scant. This narrative review aims to bridge this gap in knowledge concerning the interplay between dyslipidemia, cholangitis, and hepatic steatosis. By addressing this gap, clinicians can better identify patients at heightened risk of future major cardiovascular events, facilitating more targeted interventions and management strategies. The review delves into the intricate relationships between dyslipidemia and these hepatic and biliary clinical conditions, shedding light on potential mechanisms underlying their associations. Understanding these complex interactions is crucial for optimizing cardiovascular risk assessment as well and devising tailored treatment approaches for patients with dyslipidemia and associated hepatic disorders. Moreover, elucidating these connections empowers clinicians with the knowledge needed to navigate the multifaceted landscape of cardiovascular risk assessment and management effectively. By exploring the intricate relationships between dyslipidemia, cholangitis, and hepatic steatosis (without forgetting the possible clinical consequences of hepatic steatosis itself), this review not only contributes to the existing body of knowledge but also offers insights into potential avenues for further research and clinical practice. Thus, it serves as a valuable resource for healthcare professionals striving to enhance patient care and outcomes in the context of cardiovascular disease and associated hepatic conditions.

Bile acid (BA) receptors (e.g., farnesoid X-activated receptor, muscarinic receptor) are expressed in cardiomyocytes, endothelial cells, and vascular smooth muscle cells, indicating the relevance of BAs to cardiovascular disease (CVD). Hydrophobic BAs are cardiotoxic, while hydrophilic BAs are cardioprotective. For example, fetal cardiac insufficiency in maternal intrahepatic cholestasis during pregnancy, and the degree of fetal cardiac abnormality, is closely related to the level of hydrophobic BAs in maternal blood and infant blood. However, ursodeoxycholic acid (the most hydrophilic BA) can reverse/prevent these detrimental effects of increased levels of hydrophobic BAs on the heart. The gut microbiota (GM) and GM metabolites (especially secondary BAs) have crucial roles in hypertension, atherosclerosis, unstable angina, and heart failure. Herein, we describe the relationship between CVD and the GM at the BA level. We combine the concept of the "microbiota-gut-heart axis" (MGHA) and postulate the role and mechanism of BAs in CVD development. In addition, the strategies for treating CVD with BAs under the MGHA are proposed.

Primary sclerosing cholangitis (PSC) is a bile duct disorder characterized by ductular reaction, hepatic inflammation, and liver fibrosis. The pathogenesis of PSC is still undefined, and treatment options for patients are limited. Previous clinical trials evaluated drug candidates targeting various cellular functions and pathways, such as bile acid signaling and absorption, gut bacteria and permeability, and lipid metabolisms. However, most of phase III clinical trials for PSC were disappointing, except vancomycin therapy, and there are still no established medications for PSC with efficacy and safety confirmed by phase IV clinical trials.

This review summarizes the currently ongoing or completed clinical studies for PSC, which are phase II or further, and discusses therapeutic targets and strategies, limitations, and future directions and possibilities of PSC treatments. A literature search was conducted in PubMed and ClinicalTrials.gov utilizing the combination of the searched term 'primary sclerosing cholangitis' with other keywords, such as 'clinical trials,' 'antibiotics,' or drug names. Clinical trials at phase II or further were included for consideration.

Only vancomycin demonstrated promising therapeutic effects in the phase III clinical trial. Other drug candidates showed futility or inconsistent results, and the search for novel PSC treatments is still ongoing.

How antimitochondrial antibody (AMA)-positive patients evolve to have primary biliary cholangitis (PBC) in viral hepatitis-endemic areas is unknown.

We aimed to investigate this evolution in Taiwan.

A 16-year medical center-based cohort study of 2,095,628 subjects was conducted in Taiwan, an Asian country endemic to viral hepatitis. AMA-positive subjects were those with positive AMA with alkaline phosphatase (ALP) ⩽1.5 times the upper limit of normal (ULN), and PBC was defined as positive AMA with ALP >1.5 × ULN.

AMA-positive subjects had a lower average age- and sex-adjusted prevalence than PBC patients (4.68/105 versus 11.61/105, p = 0.0002), but their incidence was comparable (0.99/105 versus 1.12/105, p = 0.36). The former group had a borderline significantly lower mean age (56.59 years versus 58.10 years, p = 0.06) and a lower female-to-male ratio (2.85:1 versus 5.44:1, p < 0.0001). Both AMA-positive subjects (prevalence change: 20.0%, p < 0.01; incidence change: -9.2%, p < 0.01) and PBC patients (prevalence change: 14.6%, p < 0.01; incidence change: -4.7%, p < 0.01) prevalence rate increased but the incidence rate decreased. Among the 423 AMA-positive subjects, 77 (18.2%) developed PBC, for a mean duration of 1.757 years. Compared with AMA-positive subjects, PBC patients had similar concurrent chronic hepatitis B (CHB) rates (2.7% versus 4.3%, p = 0.197) but lower chronic hepatitis C (CHC) rates (3.69% versus 15.60%, p < 0.01).

PBC was more prevalent than AMA-positive subjects, and PBC patients had a higher female-to-male ratio than AMA-positive subjects, of whom 18.2% developed PBC (mean lag: 1.757 years). Upward trends in prevalence rates and downward trends in incidence rates were noted for both AMA-positive subjects and PBC. CHB was rare, CHC was more prevalent among PBC patients than the general population, and CHC was less prevalent among PBC than among AMA-positive subjects.

High-dose Obeticholic acid exhibits promise for non-alcoholic fatty liver disease (NAFLD) treatment but can induce lipotoxicity. Our study sought to understand this mechanism and propose a solution.

In a non-alcoholic fatty liver disease (NAFLD) model induced by a high-fat diet in FXR-/- mice, we pinpointed that FXR regulated the expression of ACOX1 through RNA-Seq analysis. In the livers of FXR-/- mice, both ACOX1 mRNA and protein expression notably decreased. In both HL-7702 and HEP-G2 cells, the silencing of FXR through shRNA plasmids decreased ACOX1 expression, while FXR activation with GW4064 increased it. These effects were reversible with the ACOX1-specific inhibitor, 10,12-Tricosadiynoic acid. In the NAFLD model of FXR-/- mice, The activation of ACOX1 is correlated with elevated serum LDL, triglycerides, and aggravated hepatic steatosis. However, the combination of 10,12-Tricosadiynoic acid with low-dose obeticholic acid effectively treated hepatic steatosis, reducing LDL levels in the NAFLD model of wild-type mice. This combination therapy demonstrated efficacy comparable to high-dose obeticholic acid alone. Notably, the combined drug regimen treats hepatic steatosis by inhibiting the IL-1β and α-SMA pathways in NAFLD.

Combining ACOX1-specific inhibitors with low-dose obeticholic acid effectively treats high-fat diet-induced hepatic steatosis and reduces serum LDL. This approach enhances the therapeutic effects of obeticholic acid and mitigates its lipotoxicity by inhibiting the IL-1β and α-SMA pathways.

Advances in the understanding of bile salt synthesis, transport and signalling show the potential of modulating bile salt homeostasis as a therapeutic strategy in cholestatic liver diseases. Here, recent developments in (pre)clinical research in this field is summarized and discussed.

Inhibition of the apical sodium-dependent bile salt transporter (ASBT) and Na + -taurocholate cotransporting polypeptide (NTCP) seems effective against cholestatic liver diseases, as well as Farnesoid X receptor (FXR) agonism or a combination of both. While approved for the treatment of primary biliary cholangitis (PBC) and intrahepatic cholestasis of pregnancy (ICP), ursodeoxycholic acid (UDCA) has retrospectively shown carefully promising results in primary sclerosing cholangitis (PSC). The side chain shortened derivate norUDCA is of further therapeutic interest since its mechanisms of action are independent of the bile salt transport machinery. In the pathogenesis of sclerosing cholangiopathies, a skewed T-cell response with alterations in gut microbiota and bile salt pool compositions are observed. In PSC pathogenesis, the bile salt receptor Takeda G-protein-coupled receptor 5 (TGR5) in cholangiocytes is implicated, whilst in immunoglobulin G4-related cholangitis the autoantigens annexin A11 and laminin 511-E8 are involved in protecting cholangiocytes.

Modulating bile salt homeostasis has proven a promising treatment strategy in models of cholestasis and are continuously being further developed. Confirmatory clinical studies are needed in order to assess the proposed treatment strategies in patients allowing for a broader therapeutic arsenal in the future.

Human fibroblast growth factor 19 (FGF19, or FGF15 in rodents) plays a central role in controlling bile acid (BA) synthesis through a negative feedback mechanism. This process involves a postprandial crosstalk between the BA-activated ileal farnesoid X receptor and the hepatic Klotho beta (KLB) coreceptor complexed with fibrobalst growth factor receptor 4 (FGFR4) kinase. Additionally, FGF19 regulates glucose, lipid, and energy metabolism by coordinating responses from functional KLB and FGFR1-3 receptor complexes on the periphery. Pharmacologically, native FGF19 or its analogs decrease elevated BA levels, fat content, and collateral tissue damage. This makes them effective in treating both cholestatic diseases such as primary biliary or sclerosing cholangitis (PBC or PSC) and metabolic abnormalities such as nonalcoholic steatohepatitis (NASH). However, chronic administration of FGF19 drives oncogenesis in mice by activating the FGFR4-dependent mitogenic or hepatic regenerative pathway, which could be a concern in humans. Agents that block FGF19 or FGFR4 signaling have shown great potency in preventing FGF19-responsive hepatocellular carcinoma (HCC) development in animal models. Recent phase 1/2 clinical trials have demonstrated promising results for several FGF19-based agents in selectively treating patients with PBC, PSC, NASH, or HCC. This review aims to provide an update on the clinical development of both analogs and antagonists targeting the FGF19-FGFR4 signaling pathway for patients with cholestatic, metabolic, and cancer diseases. We will also analyze potential safety and mechanistic concerns that should guide future research and advanced trials.

Primary biliary cholangitis (PBC) is a chronic cholestatic liver disease. The most common antibody associated with PBC is the anti-mitochondrial antibody (AMA), present in 90% to 95% of patients. For patients who are AMA-negative, novel biomarkers, such as antinuclear antibody-specific antibodies Sp100 and gp210 and anti-kelch-like-12 and anti-hexokinase-1 antibodies, may further aid in the diagnosis of PBC. Several laboratory methods, including immunofluorescence, enzyme-linked immunosorbent assay, immunoblotting, and bead-based assays, exist to evaluate for the presence of antibodies. This article describes various methods used to evaluate antibodies as well as describe the antibodies present in PBC.

Ursodeoxycholic acid (UDCA) is the first-line treatment of primary biliary cholangitis (PBC). Long-term UDCA use significantly reduces progression to cirrhosis. UDCA improves liver enzymes and transplant-free survival rates. Despite the association between PBC and hyperlipidemia, treatment is indicated under specific circumstances with statins and fibrates being safe options. Osteoporosis, which is frequently seen, is usually managed based on data from postmenopausal women. Sicca syndrome is treated similarly to its standalone condition with the use of hydroxypropyl methylcellulose eye drops and anticholinergic drugs.

Up to 40% of UDCA-treated patients do not have an adequate clinical response. Farnesoid X receptor agonists, peroxisome proliferator-activated receptor agonists, and fibroblast growth factor 19 analogs were developed as adjunctive therapy. The aim of this network meta-analysis was to compare the efficacy of these drugs as add-on therapy for patients with primary biliary cholangitis (PBC) refractory to UDCA in improving ALP levels.

We searched PubMed, Embase, Web of Science, and the Cochrane Library for eligible studies until 1 December 2023. Randomized controlled trials, cohort studies, and case-control studies comparing the efficacy of different combination treatments and UDCA monotherapy in UDCA-refractory PBC patients were included in the analysis. Cumulative probability was used to rank the included treatments.

A total of 23 articles were eligible for our network meta-analysis. In terms of improving ALP levels, In terms of improving ALP biochemical levels, bezafibrate combined with UDCA (MD 104.49, 95% CI 60.41, 161.92), fenofibrate combined with UDCA (MD 87.81, 95% CI (52.34, 129.79), OCA combined with UDCA (MD 65.21, 95% CI 8.99, 121.80), seladelpar combined with UDCA (MD 117.39, 95% CI 19.97, 213.95), elafibranor combined with UDCA (MD 140.73, 95% CI 74.34, 209.98), saroglitazar combined with UDCA (MD 132.09, 95% CI 13.99, 247.04) was more effective than UDCA monotherapy. Elafibranor in combination with UDCA was the most likely (32%) to be the optimal drug regimen.

As second-line therapy for UDCA-refractory PBC, PPAR agonists were more effective than any other drugs with other mechanisms in improving ALP biochemical levels, with elafibranor being the best.

Global profiling of bile acids (BAs) is imperative for understand their function and disease pathogenesis. But it is still a challenging task, as the collision-induced dissociation (CID) fragment ions of unconjugated BAs showed low ion intensities to insufficient analysis. Herein, we developed a highly sensitive method for pseudotargeted profiling of BAs by chemical derivatization. In the developed method, a labeling reagent, 2-dimethylaminoethylamine (DMED), was adopted to label the carboxyl group of BAs. The results demonstrated that the detection sensitivities of unconjugated BAs were increased by 4-200 folds after DMED-labeling. Moreover, to profile other potential BAs not included in the 91 known targets, diverse survey experiments were performed on Qtrap-MS to search BAs for both precursor and fragment ion species, and retention index (RI) strategy was adopted to facilitate the identification of isomers. Finally, MRM-based LC-MS/MS method was validated for the pseudotargeted profiling of the BAs submetabolome with good linearity (r2 ≥ 0.990 for 89 known BAs) and high sensitivity (0.05-0.5 ng/mL for unconjugated BAs), covering unconjugated, glycine, taurine, sulfuric acid, glucuronic acid, and as well as those doubly-conjugated with above types. With this method, a total of 107 BAs, covering 54 BAs identified by authentic standards and 53 BAs candidates, were successfully determined in human serum of women with intrahepatic cholestasis of pregnancy (ICP). Multivariate analysis revealed deferentially expressed BAs. ICP disease altered the BAs profile with a reduced proportion of unconjugated, sulfate- and doubly-conjugated BAs and an increased proportion of glycine and taurine conjugates. Altered proportion and profile of BAs in ICP groups were gradually recovered during the ursodeoxycholic acid (UDCA) therapy. Overall, the strategy of DMED-labeling technique combined with diverse survey experiments is sufficiently sensitive and robust to comprehensively analysis of metabolic profiling of BAs in human serum.

Cholestasis is characterized by hepatic accumulation of cytotoxic bile acids (BAs), which often subsequently leads to liver injury, inflammation, fibrosis, and liver cirrhosis. Fibroblast growth factor 21 (FGF21) is a liver-secreted hormone with pleiotropic effects on the homeostasis of glucose, lipid, and energy metabolism. However, whether hepatic FGF21 plays a role in cholestatic liver injury remains elusive. We found that serum and hepatic FGF21 levels were significantly increased in response to cholestatic liver injury. Hepatocyte-specific deletion of Fgf21 exacerbated hepatic accumulation of BAs, further accentuating liver injury. Consistently, administration of rFGF21 ameliorated cholestatic liver injury caused by α-naphthylisothiocyanate (ANIT) treatment and Mdr2 deficiency. Mechanically, FGF21 activated a hepatic FGFR4-JNK signaling pathway to decrease Cyp7a1 expression, thereby reducing hepatic BAs pool. Our study demonstrates that hepatic FGF21 functions as an adaptive stress-responsive signal to downregulate BA biosynthesis, thereby ameliorating cholestatic liver injury, and FGF21 analogs may represent a candidate therapy for cholestatic liver diseases.

Seladelpar is a potent and selective peroxisome proliferator-activated receptor-δ agonist that targets multiple cell types involved in primary biliary cholangitis (PBC), leading to anti-cholestatic, anti-inflammatory and anti-pruritic effects.

To evaluate the long-term safety and efficacy of seladelpar in patients with PBC.

In an open-label, international, long-term extension study, patients with PBC completing seladelpar lead-in studies continued treatment. Seladelpar was taken orally once daily at doses of 5 or 10 mg with dose adjustment permitted for safety or tolerability. The primary analysis was for safety and the secondary efficacy analysis examined biochemical markers of cholestasis and liver injury. The study was terminated early due to the unexpected histological findings in a concurrent study for non-alcoholic steatohepatitis, which were subsequently found to predate treatment. Safety and efficacy data were analysed through 2 years.

There were no serious treatment-related adverse events observed among 106 patients treated with seladelpar for up to 2 years. There were four discontinuations for safety, one possibly related to seladelpar. Among 53 patients who completed 2 years of seladelpar, response rates increased from years 1 to 2 for the composite endpoint (alkaline phosphatase [ALP] <1.67 × ULN, ≥15% decrease in ALP, and total bilirubin ≤ULN) and ALP normalisation from 66% to 79% and from 26% to 42%, respectively. In those with elevated bilirubin at baseline, 43% achieved normalisation at year 2.

Seladelpar was safe, and markedly improved biochemical markers of cholestasis and liver injury in patients with PBC. These effects were maintained or improved throughout the second year.

gov: NCT03301506; Clinicaltrialsregister.eu: 2017-003910-16.

Farnesoid X receptor (FXR) was identified as an orphan nuclear receptor resembling the steroid receptor in the late '90s. Activation of FXR is a crucial step in many physiological functions of the liver. A vital role of FXR is impacting the amount of bile acids in the hepatocytes, which it performs by reducing bile acid synthesis, stimulating the bile salt export pump, and inhibiting its enterohepatic circulation, thus protecting the hepatocytes against the toxic accumulation of bile acids. Furthermore, FXR mediates bile acid biotransformation in the intestine, liver regeneration, glucose hemostasis, and lipid metabolism. In this review, we first discuss the mechanisms of the disparate pleiotropic actions of FXR agonists. We then delve into the pharmacokinetics of Obeticholic acid (OCA), the first-in-class selective, potent FXR agonist. We additionally discuss the clinical journey of OCA in humans, its current evidence in various human diseases, and its plausible roles in the future.

Causality assessment of suspected drug-induced liver injury (DILI) during metabolic dysfunction-associated steatohepatitis (MASH) clinical trials can be challenging, and liver biopsies are not routinely performed as part of this evaluation. While the field is moving away from liver biopsy as a diagnostic and prognostic tool, information not identified by non-invasive testing may be provided on histology.

To address the appropriate utilisation of liver biopsy as part of DILI causality assessment in this setting.

From 2020 to 2022, the Liver Forum convened a series of webinars on issues pertaining to liver biopsy during MASH trials. The Histology Working Group was formed to generate a series of consensus documents addressing these challenges. This manuscript focuses on liver biopsy as part of DILI causality assessment.

Expert opinion, guidance and recommendations on the role of liver biopsy as part of causality assessment of suspected DILI occurring during clinical trials for a drug(s) being developed for MASH are provided. Lessons learned from prior MASH programs are reviewed and gaps identified.

Although there are no pathognomonic features, histologic evaluation of suspected DILI during MASH clinical trials may alter patient management, define the pattern and severity of injury, detect findings that favour a diagnosis of DILI versus MASH progression, identify prognostic features, characterise the clinicopathological phenotype of DILI, and/or define lesions that influence decisions about trial discontinuation and further development of the drug.