obeticholic-acid and Cholestasis

Currently, there is no pharmacotherapy for non-alcoholic steatohepatitis (NASH), a common liver disorder. In contrast, primary biliary cholangitis (PBC) is a chronic cholestatic liver disease for which ursodeoxycholic acid (UDCA) is the drug of choice. However, 50% of PBC patients may not respond to UDCA. Obeticholic acid (OCA) is emerging as a vital pharmacotherapy for these chronic disorders. We aimed to analyse the safety and efficacy of OCA.. We performed an extensive search of electronic databases from 01/01/2000 to 31/03/2020. We included randomized controlled trials of OCA in patients with NASH, PBC, and primary sclerosing cholangitis (PSC). We assessed the histological improvement in NASH, reduction in alkaline phosphatase (≤1.67 ULN) in PBC, and the adverse effects of OCA.. Seven RCTs (n = 2834) were included. Of the total RCTs, there were three on both NASH and PBC and one on PSC. OCA improved NASH fibrosis [OR: 1.95 (1.47-2.59; p < 0.001)]. With the 10 mg OCA dose, the odds of improvement was 1.61 (1.03-2.51; p = 0.03), while with the 25 mg dose, it was 2.23 (1.55-3.18; p < 0.001). However, 25 mg OCA led to significant adverse events and discontinuation of the drug [2.8 (1.42-3.02); p < 0.001)] compared with 10 mg OCA [0.95 (0.6-1.5); p = 0.84] in NASH patients. In PBC patients, the response to 5 mg OCA was better than with the higher doses [5 mg: 7.66 (3.12-18.81; p < 0.001), 10 mg: 5.18 (2-13.41; p = 0.001), 25 mg: 2.36 (0.94-5.93; p = 0.06), 50 mg: 4.08 (1.05-15.78; p = 0.04)]. The risk of pruritus was lowest with 5 mg OCA.. Lower doses of OCA are effective and safe in NASH and cholestatic liver disease. While 10 mg OCA is effective for NASH fibrosis regression, only 5 mg OCA is required for PBC.

Topics: Chenodeoxycholic Acid; Cholestasis; Humans; Liver Cirrhosis, Biliary; Non-alcoholic Fatty Liver Disease; Pharmaceutical Preparations; Ursodeoxycholic Acid

Primary biliary cholangitis is a chronic liver disorder characterized by progressive cholestasis that may evolve to liver cirrhosis. While ursodeoxycholic acid is the treatment of choice, around 30% of patients do not respond to this therapy. These patients have a poorer prognosis, hence should be identified early in order to be offered therapy options. Along these lines, improved understanding of the condition's pathophysiology has allowed the development of newer drugs, including obeticholic acid and fibrates. This review offers a perspective on risk stratification and treatment for these patients, from ursodeoxycholic acid to second-line treatments.

Topics: Adult; Age Factors; Alkaline Phosphatase; Biomarkers; Budesonide; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Cholestasis; Disease Progression; Fibric Acids; Glucocorticoids; Humans; Liver Cirrhosis; Liver Transplantation; Middle Aged; Risk Assessment; Risk Factors; Sex Factors; Treatment Failure; Ursodeoxycholic Acid

Cholestatic liver diseases encompass a broad spectrum of pathologies, with the core injury occurring at the level of cholangiocytes and progressing to hepatic fibrosis and liver dysfunction. Primary biliary cholangitis and primary sclerosing cholangitis are the most significant progressive cholangiopathies in adults. Although rare, they commonly evolve to liver failure and need for liver transplantation. Despite recent advances in the basic knowledge of these cholangiopathies, the pathogenesis is still elusive. Targeted treatments to prevent disease progression and to preclude malignancy are not yet available. This review will address the general clinical features of both diseases, analyze their commonalities and differences, and provide a state-of-the art overview of the currently available therapeutics.

Topics: Adult; Biliary Tract; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis, Sclerosing; Cholestasis; Clinical Trials as Topic; Disease Progression; Drug Therapy, Combination; End Stage Liver Disease; Humans; Immunologic Factors; Life Expectancy; Prevalence; Prognosis; Treatment Outcome; Ursodeoxycholic Acid

While bile acids are important for both digestion and signalling, hydrophobic bile acids can be harmful, especially when in high concentrations. Mechanisms for the protection of cholangiocytes against bile acid cytotoxicity include negative feedback loops via farnesoid X nuclear receptor (FXR) activation, the bicarbonate umbrella, cholehepatic shunting and anti-inflammatory signalling, among others. By altering or overwhelming these defence mechanisms, cholestatic diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) can further progress to biliary cirrhosis, end-stage liver disease and death or liver transplantation. While PBC is currently treated with ursodeoxycholic acid (UDCA) and obeticholic acid (OCA), many fail treatment, and we have yet to find an effective therapy for PSC. Novel therapies under evaluation target nuclear and surface receptors including FXR, transmembrane G-protein-coupled receptor 5 (TGR5), peroxisome proliferator-activated receptor (PPAR) and pregnane X receptor (PXR). Modulation of these receptors leads to altered bile composition, decreased cytotoxicity, decreased inflammation and improved metabolism. This review summarizes our current understanding of the role of bile acids in the pathophysiology of cholestatic liver diseases, presents the rationale for already approved medical therapies and discusses novel pharmacologic therapies under investigation.

Topics: Bile Acids and Salts; Budesonide; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis, Sclerosing; Cholestasis; Drug Therapy, Combination; Elasticity Imaging Techniques; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis, Biliary; Receptors, Cytoplasmic and Nuclear; Ursodeoxycholic Acid

In the long-term course chronic cholestasis regularly leads to fibrotic restructuring and ultimately to functional failure of the liver, independent of the cause. Cholestatic diseases are often clinically asymptomatic. In order to avoid progression, early diagnosis of the underlying disease and a targeted therapy are therefore decisive. The differential diagnoses of chronic cholestasis are broad; therefore, algorithms are of assistance in the diagnostic work-up. A better understanding of the pathogenesis is now leading to the development of new therapeutic agents in addition to ursodeoxycholic acid, which has long been known for its anticholestatic effects. Obeticholic acid and, in the near future, bezafibrate are therapeutic options. The possibilities for genetic diagnostics of unclear cholestasis syndromes improve the understanding of the pathogenesis of many diseases and are being introduced increasingly earlier into the clinical routine.

Topics: Adult; Bezafibrate; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholestasis; Diagnosis, Differential; Humans; Liver Diseases; Ursodeoxycholic Acid

Primary biliary cholangitis (PBC) is an autoimmune disease of the liver characterized by destruction and inflammation of the intrahepatic bile ducts. The disease affects mainly women. The disease is often discovered through abnormal alkaline phosphatase (ALP) activity, and is confirmed when anti-mitochondrial antibodies (AMA) are present. The etiology of PBC is poorly understood. Cigarette smoking, immune dysregulation, nail polish, urinary tract infections, and low socioeconomic status have been implicated but none have been confirmed. Genome wide association studies (GWAS) have disclosed strong associations between certain human leukocyte antigen (HLA) alleles and PBC. PBC can progress to cirrhosis and end-stage liver disease. Hepatocellular carcinoma (HCC) develops in up to 3.5% of PBC patients. Ursodeoxycholic acid (UDCA) is the only medication approved for the treatment of PBC. The use of UDCA in PBC delays histological progression and extends the transplant-free survival. 40% of PBC patients do not respond adequately to UDCA, and these patients are at high risk for serious complications. Therefore, there is a critical need for more effective therapies for this problematic disease. Multiple other agents have either been or are currently being studied as therapeutic options in UDCA non-responder PBC patients. Six-ethyl chenodeoxycholic acid (6-ECDCA), a potent farnesoid X receptor (FXR) agonist, has shown anti-cholestatic activity in rodent models of cholestasis. Obeticholic acid (OCA, 6-ECDCA, or INT-747), a first-in-class FXR agonist, has been examined in PBC patients with inadequate response to UDCA, and shown promising results. Particularly, initial clinical trials have demonstrated that the use of OCA (in addition to UDCA) in PBC patients with inadequate response to UDCA led to significant reduction of serum alkaline phosphatase (ALP, an important prognostic marker in PBC). More recently, the results of a randomized clinical trial of OCA monotherapy in PBC reported significant reduction of ALP in the treatment group compared to placebo.. This review covers the preclinical and clinical studies of OCA in PBC. In addition, other alternative therapies that are currently being examined in PBC patients will also be discussed in this review. A literature search was carried out using the PubMed database.. If approved by the U.S. FDA, OCA will likely be an important alternative add-on therapy in PBC patients who have inadequate response to UDCA.

Topics: Animals; Autoimmune Diseases; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Cholestasis; End Stage Liver Disease; Genome-Wide Association Study; Humans; Liver Cirrhosis, Biliary; Randomized Controlled Trials as Topic; Ursodeoxycholic Acid

Topics: Animals; Azepines; Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholestasis; Drug Evaluation, Preclinical; Gastrointestinal Agents; Hepatitis, Autoimmune; Humans; Hypertension, Portal; Indoles; Isoxazoles; Liver Cirrhosis, Alcoholic; Liver Cirrhosis, Biliary; Liver Diseases; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Receptors, Cytoplasmic and Nuclear; Ursodeoxycholic Acid

Bile acids are end products of cholesterol metabolism. They are exclusively synthesised by the liver and subsequently secreted via the bile duct into the intestine to facilitate the absorption of dietary fat and fat-soluble vitamins. Nuclear receptors are ligand-activated transcription factors. The farnesoid X receptor (FXR) has recently been identified as a bile acid-activated nuclear receptor. FXR controls bile-acid synthesis, conjugation and transport, as well as lipid metabolism. Recent advances in FXR biology demonstrate that FXR may represent a valuable target for the identification of novel drugs to treat dyslipidaemia and cholestasis. However, for therapeutic purposes the development of selective FXR modulators, which only activate or inhibit specific FXR target genes and as such induce specific responses, will be required.

Topics: Animals; Benzene Derivatives; Caprylates; Chenodeoxycholic Acid; Cholestasis; DNA-Binding Proteins; Humans; Hyperlipidemias; Hypolipidemic Agents; Molecular Structure; Phenyl Ethers; Receptors, Cytoplasmic and Nuclear; Transcription Factors

Obeticholic acid (OCA), a potent farnesoid X receptor agonist, was studied as monotherapy in an international, randomized, double-blind, placebo-controlled phase 2 study in patients with primary biliary cholangitis who were then followed for up to 6 years. The goals of the study were to assess the benefit of OCA in the absence of ursodeoxycholic acid, which is relevant for patients who are intolerant of ursodeoxycholic acid and at higher risk of disease progression. Patients were randomized and dosed with placebo (n = 23), OCA 10 mg (n = 20), or OCA 50 mg (n = 16) given as monotherapy once daily for 3 months (1 randomized patient withdrew prior to dosing). The primary endpoint was the percent change in alkaline phosphatase from baseline to the end of the double-blind phase of the study. Secondary and exploratory endpoints included change from baseline to month 3/early termination in markers of cholestasis, hepatocellular injury, and farnesoid X receptor activation. Efficacy and safety continue to be monitored through an ongoing 6-year open-label extension (N = 28). Alkaline phosphatase was reduced in both OCA groups (median% [Q1, Q3], OCA 10 mg -53.9% [-62.5, -29.3], OCA 50 mg -37.2% [-54.8, -24.6]) compared to placebo (-0.8% [-6.4, 8.7]; P < 0.0001) at the end of the study, with similar reductions observed through 6 years of open-label extension treatment. OCA improved many secondary and exploratory endpoints (including γ-glutamyl transpeptidase, alanine aminotransferase, conjugated bilirubin, and immunoglobulin M). Pruritus was the most common adverse event; 15% (OCA 10 mg) and 38% (OCA 50 mg) discontinued due to pruritus.. OCA monotherapy significantly improved alkaline phosphatase and other biochemical markers predictive of improved long-term clinical outcomes. Pruritus increased dose-dependently with OCA treatment. Biochemical improvements were observed through 6 years of open-label extension treatment. (Hepatology 2018;67:1890-1902).

Topics: Adult; Alkaline Phosphatase; Chenodeoxycholic Acid; Cholestasis; Double-Blind Method; Female; Follow-Up Studies; Humans; Liver Cirrhosis, Biliary; Male; Middle Aged; Receptors, Cytoplasmic and Nuclear; Treatment Outcome

Patients with cholestatic liver disease, including those with primary biliary cholangitis, can experience symptoms of impaired cognition or brain fog. This phenomenon remains unexplained and is currently untreatable. Bile duct ligation (BDL) is an established rodent model of cholestasis. In addition to liver changes, BDL animals develop cognitive symptoms early in the disease process (before development of cirrhosis and/or liver failure). The cellular mechanisms underpinning these cognitive symptoms are poorly understood. Herein, the study explored the neurocognitive symptom manifestations, and tested potential therapies, in BDL mice, and used human neuronal cell cultures to explore translatability to humans. BDL animals exhibited short-term memory loss and showed reduced astrocyte coverage of the blood-brain barrier, destabilized hippocampal network activity, and neuronal senescence. Ursodeoxycholic acid (first-line therapy for most human cholestatic diseases) did not reverse symptomatic or mechanistic aspects. In contrast, obeticholic acid (OCA), a farnesoid X receptor agonist and second-line anti-cholestatic agent, normalized memory function, suppressed blood-brain barrier changes, prevented hippocampal network deficits, and reversed neuronal senescence. Co-culture of human neuronal cells with either BDL or human cholestatic patient serum induced cellular senescence and increased mitochondrial respiration, changes that were limited again by OCA. These findings provide new insights into the mechanism of cognitive symptoms in BDL animals, suggesting that OCA therapy or farnesoid X receptor agonism could be used to limit cholestasis-induced neuronal senescence.

Topics: Animals; Bile Ducts; Chenodeoxycholic Acid; Cholestasis; Humans; Ligation; Liver; Memory, Short-Term; Mice

Di-(2-ethylhexyl)-phthalate (DEHP) is a ubiquitous environmental pollutant and is widely used in industrial plastics. Intrahepatic cholestasis of pregnancy (ICP), distinguished by maternal pruritus and elevated serum bile acid levels, is linked to unfavorable pregnancy consequences. Few studies have investigated the potential effect of gestational DEHP exposure on the cholestasis in pregnant female mice, and the underlying mechanisms remain unclear. In the present study, a mouse model of cholestasis during pregnancy was established by DEHP exposure. We found that DEHP induces elevated bile acid levels by affecting bile acid synthesis and transporter receptor expression in the maternal liver and placenta of pregnant female mice, ultimately leading to intrauterine growth restriction (IUGR). In addition, DEHP changed the bile acid composition of maternal serum and liver as well as placenta and amniotic fluid in pregnant female mice; Importantly, we found that DEHP down-regulates the expression of farnesoid X receptor (FXR), which is considered to be a bile acid receptor. FXR agonist obeticholic acid (OCA) effectively alleviated the adverse effects of DEHP on pregnant female mice. While, OCA itself had no adverse effects on normal pregnant female mice. In summary, DEHP could induces bile acid disorder and IUGR in pregnant female mice by affect FXR, which was reversed by OCA.

Topics: Animals; Bile Acids and Salts; Cholestasis; Diethylhexyl Phthalate; Female; Fetal Growth Retardation; Humans; Mice; Pregnancy

Obeticholic acid (OCA) was approved for the treatment of primary biliary cholangitis (PBC) patients, as it can significantly improve the level of serum alkaline phosphatase. However, OCA-induced liver injury in PBC patients puts them at risk of acute chronic liver failure, thus limiting the clinical application of OCA. Osteopontin (OPN), an extracellular cell matrix molecule, is highly induced in many cholestatic liver diseases. Herein we explored whether liver injury exacerbation by OCA was related to OPN.. Bile duct ligation (BDL) mice were treated with OCA (40 mg/kg) to evaluate its effect on liver injury and OPN involvement. Enzyme-linked immunosorbent assay, western blot, immunohistochemistry, and other assays were used to detect OPN levels in serum and liver. Immunohistochemistry, and immunofluorescence, among other assays, were used to evaluate the extent of ductular reaction. The extent of fibrosis was also determined using various assays, such as immunohistochemistry, quantitative real-time PCR (qPCR), and hydroxyproline assays.. OPN was overexpressed in the liver of BDL mice treated with OCA. OCA induced overexpression of OPN exacerbated ductular reaction, fibrosis, and liver inflammation, and reduced hepatocyte proliferation.. Upon liver injury, OCA upregulates the expression of OPN in the liver and accelerates disease progression. This mechanism helps explain the risk of liver damage associated with OCA.

Topics: Alkaline Phosphatase; Animals; Chenodeoxycholic Acid; Cholestasis; Fibrosis; Hydroxyproline; Liver; Mice; Osteopontin

ATP-binding cassette, subfamily B member 11 (ABCB11) is an efflux transporter for bile acids on the liver canalicular membrane. The expression of this transporter is reduced in cholestasis; however, the mechanisms contributing to this reduction are unclear. In this study, we sought to determine whether miR-199a-5p contributes to the depletion of ABCB11/Abcb11 in cholestasis in mice. In a microRNA (miRNA) screen of mouse liver after common bile duct ligation (CBDL), we found that miR-199a-5p was significantly upregulated by approximately fourfold. In silico analysis predicted that miR-199a-5p would target the 3'-untranslated region (3'-UTR) of ABCB11/Abcb11 mRNA. The expression of ABCB11-3'-UTR luciferase construct in Huh-7 cells was markedly inhibited by cotransfection of a miRNA-199a-5p mimic, which was reversed by an miRNA-199a-5p mimic inhibitor. We also show treatment of mice after CBDL with the potent nuclear receptor FXR agonist obeticholic acid (OCA) significantly increased Abcb11 mRNA and protein and decreased miR-199a-5p expression. Computational mapping revealed a well-conserved FXR-binding site (FXRE) in the promoter of the gene encoding miR-199a-5, termed miR199a-2. Electromobility shift, chromatin immunoprecipitation, and miR199a-2 promoter-luciferase assays confirmed that this binding site was functional. Finally, CBDL in mice led to depletion of nuclear repressor NcoR1 binding at the miR199a-2 promoter, which facilitates transcription of miR199a-2. In CBDL mice treated with OCA, NcoR1 recruitment to the miR199a-2 FXRE was maintained at levels found in sham-operated mice. In conclusion, we demonstrate that miR-199a-5p is involved in regulating ABCB11/Abcb11 expression, is aberrantly upregulated in obstructive cholestasis, and is downregulated by the FXR agonist OCA.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; Chenodeoxycholic Acid; Cholestasis; Disease Models, Animal; Gene Expression Regulation; Male; Mice; Mice, Knockout; MicroRNAs; Nuclear Receptor Co-Repressor 1

Topics: Alkaline Phosphatase; Bezafibrate; Bilirubin; Chenodeoxycholic Acid; Cholestasis; Cholesterol; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Female; Humans; Hypolipidemic Agents; Liver Cirrhosis, Biliary; Liver Function Tests; Male; Middle Aged; Pruritus; Treatment Outcome

Cholestasis comprises a spectrum of liver diseases characterized by the accumulation of bile acids. Bile acids and activation of the farnesoid X receptor (FXR) can inhibit autophagy, a cellular self-digestion process necessary for cellular homeostasis and regeneration. In mice, autophagy appears to be impaired in cholestasis and induction of autophagy may reduce liver injury.. Herein, we explored autophagy in human cholestasis in vivo and investigated the underlying molecular mechanisms in vitro. FXR chromatin immunoprecipitation-sequencing and qPCR were performed in combination with luciferase promoter studies to identify functional FXR binding targets in a human cholestatic liver sample.. Autophagic processing appeared to be impaired in patients with cholestasis and in individuals treated with the FXR ligand obeticholic acid (OCA). In vitro, chenodeoxycholic acid and OCA inhibited autophagy at the level of autophagosome to lysosome fusion in an FXR-dependent manner. Rubicon, which inhibits autophago-lysosomal maturation, was identified as a direct FXR target that is induced in cholestasis and by FXR-agonistic bile acids. Genetic inhibition of Rubicon reversed the bile acid-induced impairment of autophagic flux. In contrast to OCA, ursodeoxycholic acid (UDCA), which is a non-FXR-agonistic bile acid, induced autophagolysosome formation independently of FXR, enhanced autophagic flux and was associated with reduced Rubicon levels.. In models of human cholestasis, autophagic processing is impaired in an FXR-dependent manner, partly resulting from the induction of Rubicon. UDCA is a potent inducer of hepatic autophagy. Manipulating autophagy and Rubicon may represent a novel treatment concept for cholestatic liver diseases.. Autophagy, a cellular self-cleansing process, is impaired in various forms of human cholestasis. Bile acids, which accumulate in cholestatic liver disease, induce Rubicon, a protein that inhibits proper execution of autophagy. Ursodeoxycholic acid, which is the first-line treatment option for many cholestatic liver diseases, induces hepatic autophagy along with reducing Rubicon.

Topics: Autophagosomes; Autophagy; Autophagy-Related Proteins; Chenodeoxycholic Acid; Cholestasis; Cytotoxins; Gene Knockdown Techniques; Hep G2 Cells; Humans; Liver; Lysosomes; Receptors, Cytoplasmic and Nuclear; Retrospective Studies; Signal Transduction; Transfection; Ursodeoxycholic Acid

Topics: Animals; Chenodeoxycholic Acid; Cholestasis; Hep G2 Cells; Humans; Liver; Liver Diseases; MafG Transcription Factor; Male; Mice, Inbred C57BL; Mice, Knockout; NF-E2-Related Factor 2; Rats, Wistar; Receptors, Cytoplasmic and Nuclear

Activation of farnesoid X receptor (FXR) by obeticholic acid (OCA) reduces hepatic inflammation and fibrosis in patients with primary biliary cholangitis (PBC), a life-threatening cholestatic liver failure. Inhibition of bromodomain-containing protein 4 (BRD4) also has antiinflammatory, antifibrotic effects in mice. We determined the role of BRD4 in FXR function in bile acid (BA) regulation and examined whether the known beneficial effects of OCA are enhanced by inhibiting BRD4 in cholestatic mice. Liver-specific downregulation of BRD4 disrupted BA homeostasis in mice, and FXR-mediated regulation of BA-related genes, including small heterodimer partner and cholesterol 7 alpha-hydroxylase, was BRD4 dependent. In cholestatic mice, JQ1 or OCA treatment ameliorated hepatotoxicity, inflammation, and fibrosis, but surprisingly, was antagonistic in combination. Mechanistically, OCA increased binding of FXR, and the corepressor silencing mediator of retinoid and thyroid hormone receptor (SMRT) decreased NF-κB binding at inflammatory genes and repressed the genes in a BRD4-dependent manner. In patients with PBC, hepatic expression of FXR and BRD4 was significantly reduced. In conclusion, BRD4 is a potentially novel cofactor of FXR for maintaining BA homeostasis and hepatoprotection. Although BRD4 promotes hepatic inflammation and fibrosis in cholestasis, paradoxically, BRD4 is required for the antiinflammatory, antifibrotic actions of OCA-activated FXR. Cotreatment with OCA and JQ1, individually beneficial, may be antagonistic in treatment of liver disease patients with inflammation and fibrosis complications.

Topics: Animals; Azepines; Bile Acids and Salts; Cell Cycle Proteins; Chenodeoxycholic Acid; Cholestasis; Cholesterol 7-alpha-Hydroxylase; Disease Models, Animal; Drug Interactions; Gene Knockdown Techniques; Humans; Liver; Liver Cirrhosis, Biliary; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B; Nuclear Proteins; Nuclear Receptor Co-Repressor 2; Receptors, Cytoplasmic and Nuclear; Transcription Factors; Triazoles

Intrahepatic cholestasis of pregnancy (ICP) is gestation-specific liver disease associated with liver injury and increased serum and hepatic bile acids. Although the mechanism of ICP is still not fully understood, the reproductive hormones seem to play an important role. Recent studies show that a progesterone metabolite, epiallopregnanolone sulfate (PM5S), is supraphysiologically elevated in the serum of ICP patients, indicating it may play an etiology role in ICP. Bile acid homeostasis is controlled by multiple mechanisms including farnesoid X receptor (FXR)-mediated bile acid export and synthesis. It is known that cholic acid (CA), a primary bile acid, can activate FXR, which is inhibited by PM5S, an FXR antagonist. Here we employed a mouse model of concurrent exposure of CA and PM5S-induced liver injury and determined the effects of probiotic Lactobacillus rhamnosus GG (LGG) in the prevention of the bile acid disorders and liver injury. Mice challenged with CA + PM5S had significantly increased levels of serum and hepatic bile acids and bilirubin and liver enzyme. Pretreatment with LGG significantly reduced bile acid and bilirubin levels associated with reduced liver enzyme level and mRNA expression levels of pro-inflammatory cytokines. We also showed that the beneficial effects of LGG is likely mediated by hepatic FXR activation and bile salt export pump (BSEP) upregulation. In conclusion, our results provide a rationale for the application of probiotics in the management of ICP through gut microbiota-mediated FXR activation.

Topics: Angiogenic Proteins; Animals; Bile Acids and Salts; Bilirubin; Chenodeoxycholic Acid; Cholestasis; Cholesterol 7-alpha-Hydroxylase; Cholic Acid; Cytokines; Disease Models, Animal; Gastrointestinal Microbiome; Inflammation; Lacticaseibacillus rhamnosus; Liver; Male; Mice; Mice, Inbred C57BL; Pregnanolone; Probiotics; RNA-Binding Proteins; Signal Transduction; Ursodeoxycholic Acid

The pruritus of cholestasis is a maddening complication of liver disease. Increased opioidergic tone contributes to the pruritus of cholestasis, as evidenced by the amelioration of the symptom by opiate antagonists. Obeticholic acid, an agonist of the farnesoid receptor, has been approved for the treatment of primary biliary cholangitis, a disease characterized by cholestasis; this drug is associated with pruritus, the cause of which is unknown. In animal models, bile acids, which accumulate in the body as a result of cholestasis, have been reported to cause scratching behavior mediated by the TGR5 receptor, in an opioid-dependent manner, in laboratory animals. As obeticholic acid also binds to TGR5, the pruritus caused by this drug is likely to be mediated by the opioid system. Lisophosphatidic acid, which has been reported to be increased in patients with cholestasis and pruritus, has been described to cause scratching behavior that is prevented by an opiate antagonist in laboratory animals, suggesting an opioid-receptor mediated mechanism of scratching. In summary, evidence continues to support a role of the endogenous opioid system in the pathogenesis of the pruritus of cholestasis.

Topics: Animals; Anticholesteremic Agents; Bile Acids and Salts; Chenodeoxycholic Acid; Cholestasis; Humans; Lysophospholipids; Models, Biological; Opioid Peptides; Pruritus; Receptors, G-Protein-Coupled; Receptors, Opioid

Cholestasis impairs liver regeneration following partial liver resection (PHx). Bile acid receptor farnesoid X-receptor (FXR) is a key mediator of liver regeneration. The effects of FXR agonist obeticholic acid (OCA) on liver (re)growth were therefore studied in cholestatic rats. Animals underwent sham surgery or reversible bile duct ligation (rBDL). PHx with concurrent internal biliary drainage was performed 7 days after rBDL. Animals were untreated or received OCA (10 mg/kg/day) per oral gavage from rBDL until sacrifice. After 7 days of OCA treatment, dry liver weight increased in the rBDL + OCA group, indicating OCA-mediated liver growth. Enhanced proliferation in the rBDL + OCA group prior to PHx concurred with a rise in Ki67-positive hepatocytes, elevated hepatic Ccnd1 and Cdc25b expression, and an induction of intestinal fibroblast growth factor 15 expression. Liver regrowth after PHx was initially stagnant in the rBDL + OCA group, possibly due to hepatomegaly prior to PHx. OCA increased hepatobiliary injury markers during BDL, which was accompanied by upregulation of the bile salt export pump. There were no differences in histological liver injury. In conclusion, OCA induces liver growth in cholestatic rats prior to PHx but exacerbates biliary injury during cholestasis, likely by forced pumping of bile acids into an obstructed biliary tree.

Topics: Administration, Oral; Animals; ATP Binding Cassette Transporter, Subfamily B, Member 11; cdc25 Phosphatases; Chenodeoxycholic Acid; Cholestasis; Cyclin D1; Disease Models, Animal; Fibroblast Growth Factors; Gene Expression Regulation; Liver Regeneration; Male; Organ Size; Rats

The farnesoid X receptor (FXR) is a nuclear receptor that acts as a master regulator of bile acid metabolism and signaling. Activation of FXR inhibits bile acid synthesis and increases bile acid conjugation, transport, and excretion, thereby protecting the liver from the harmful effects of bile accumulation, leading to considerable interest in FXR as a therapeutic target for the treatment of cholestasis and nonalcoholic steatohepatitis. We identified a novel series of highly potent non-bile acid FXR agonists that introduce a bicyclic nortropine-substituted benzothiazole carboxylic acid moiety onto a trisubstituted isoxazole scaffold. Herein, we report the discovery of 1 (tropifexor, LJN452), a novel and highly potent agonist of FXR. Potent in vivo activity was demonstrated in rodent PD models by measuring the induction of FXR target genes in various tissues. Tropifexor has advanced into phase 2 human clinical trials in patients with NASH and PBC.

Topics: Administration, Oral; Animals; Benzothiazoles; Biological Availability; Cholestasis; Dogs; Drug Evaluation, Preclinical; Fibroblast Growth Factors; Gene Expression Regulation; Humans; Isoxazoles; Male; Microsomes, Liver; Non-alcoholic Fatty Liver Disease; Piperidines; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Structure-Activity Relationship; Triglycerides

Primary Biliary Cholangitis, previously known as Primary Biliary Cirrhosis, is a rare disease, which mainly affects women in their fifth to seventh decades of life. It is a chronic autoimmune disease characterized by a progressive damage of interlobular bile ducts leading to ductopenia, chronic cholestasis and bile acids retention. Even if the disease usually presents a long asymptomatic phase and a slow progression, in many patients it may progress faster toward cirrhosis and its complications. The 10year mortality is greater than in diseases such as human immunodeficiency virus/Hepatitis C Virus coinfection and breast cancer. Ursodeoxycholic acid is the only treatment available today, but even if effective in counteracting the disease progression for the majority of patients, in approximately 40% is not able to decrease effectively the alkaline phosphatase, a surrogate marker of disease activity. Recently, obeticholic acid received the European Medicines Agency conditional approval, as add on treatment in patients non responders or intolerant to ursodeoxycholic acid. The present paper illustrates the opinion of a working group, composed by clinical pharmacologists, gastroenterologists/hepatologists with specific expertise on Primary Biliary Cholangitis and patient associations, on the state of the art and future perspectives of the disease management. The agreement on the document was reached through an Expert Meeting.

Topics: Chenodeoxycholic Acid; Cholagogues and Choleretics; Cholangitis; Cholestasis; Disease Progression; Drug Therapy, Combination; End Stage Liver Disease; Humans; Ursodeoxycholic Acid

Cholestasis, as a main manifestation, induces liver injury during sepsis. The farnesoid X receptor (FXR) plays an important role in regulating bile acid homeostasis. Whether FXR activation by its agonist obeticholic acid (OCA) is contributed to improve sepsis-induced liver injury remains unknown.. The aim of the present study was to investigate the effect of OCA on lipopolysaccharide (LPS)-induced acute liver injury in mice.. 8-week old male C57BL/6J mice were randomly divided into control group, LPS group, oral OCA group and LPS plus oral OCA (LPS + OCA) group. The serum and livers were collected for further analysis. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA) and total bilirubin (TBIL) were measured at indicated time after LPS administration. Liver sections were stained with hematoxylin & eosin (H&E). Orally OCA pretreatment stimulated the expression of FXR and BSEP in livers and protected mice from LPS-induced hepatocyte apoptosis and inflammatory infiltration. Consistently, LPS-induced higher serum levels of ALT, AST, TBA and TBIL were significantly reversed by OCA administration. Meanwhile, the mRNA levels of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α) and IL-6 were decreased in livers of mice in LPS + OCA group compared with LPS group. Further investigation indicated that the higher expression of ATF4 and LC3II/I were associated with the protective effect of OCA on LPS-induced liver injury.. Orally OCA pretreatment protects mice from LPS-induced liver injury possibly contributed by improved bile acid homeostasis, decreased inflammatory factors and ATF4-mediated autophagy activity in hepatocytes.

Topics: Alanine Transaminase; Animals; Apoptosis; Aspartate Aminotransferases; Bile Acids and Salts; Chemical and Drug Induced Liver Injury; Chenodeoxycholic Acid; Cholestasis; Hepatocytes; Inflammation; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred C57BL; Protective Agents; Receptors, Cytoplasmic and Nuclear

Bacterial translocation (BTL) drives pathogenesis and complications of cirrhosis. Farnesoid X-activated receptor (FXR) is a key transcription regulator in hepatic and intestinal bile metabolism. We studied potential intestinal FXR dysfunction in a rat model of cholestatic liver injury and evaluated effects of obeticholic acid (INT-747), an FXR agonist, on gut permeability, inflammation, and BTL. Rats were gavaged with INT-747 or vehicle during 10 days after bile-duct ligation and then were assessed for changes in gut permeability, BTL, and tight-junction protein expression, immune cell recruitment, and cytokine expression in ileum, mesenteric lymph nodes, and spleen. Auxiliary in vitro BTL-mimicking experiments were performed with Transwell supports. Vehicle-treated bile duct-ligated rats exhibited decreased FXR pathway expression in both jejunum and ileum, in association with increased gut permeability through increased claudin-2 expression and related to local and systemic recruitment of natural killer cells resulting in increased interferon-γ expression and BTL. After INT-747 treatment, natural killer cells and interferon-γ expression markedly decreased, in association with normalized permeability selectively in ileum (up-regulated claudin-1 and occludin) and a significant reduction in BTL. In vitro, interferon-γ induced increased Escherichia coli translocation, which remained unaffected by INT-747. In experimental cholestasis, FXR agonism improved ileal barrier function by attenuating intestinal inflammation, leading to reduced BTL and thus demonstrating a crucial protective role for FXR in the gut-liver axis.

Topics: Animals; Bacterial Translocation; Chenodeoxycholic Acid; Cholestasis; Cytokines; Escherichia coli; Gene Expression Regulation; Ileum; Male; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear

Topics: Animals; Bile Acids and Salts; Chenodeoxycholic Acid; Cholestasis; DNA-Binding Proteins; Enzyme Inhibitors; Homeostasis; Humans; Mice; Pregnane X Receptor; Rats; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Rifampin; Transcription Factors

The farnesoid X receptor (FXR), an endogenous sensor for bile acids, regulates a program of genes involved in bile acid biosynthesis, conjugation, and transport. Cholestatic liver diseases are a group of immunologically and genetically mediated disorders in which accumulation of endogenous bile acids plays a role in the disease progression and symptoms. Here, we describe the effect of 6-ethyl chenodeoxycholic acid (6-ECDCA or INT-747), a semisynthetic bile acid derivative and potent FXR ligand, in a model of cholestasis induced by 5-day administration of 17alpha-ethynylestradiol (E(2)17alpha) to rats. The exposure of rat hepatocytes to 1 microM 6-ECDCA caused a 3- to 5-fold induction of small heterodimer partner (Shp) and bile salt export pump (bsep) mRNA and 70 to 80% reduction of cholesterol 7alpha-hydroxylase (cyp7a1), oxysterol 12beta-hydroxylase (cyp8b1), and Na(+)/taurocholate cotransporting peptide (ntcp). In vivo administration of 6-ECDCA protects against cholestasis induced by E(2)17alpha. Thus, 6-ECDCA reverted bile flow impairment induced by E(2)17alpha, reduced secretion of cholic acid and deoxycholic acid, but increased muricholic acid and chenodeoxycholic acid secretion. In vivo administration of 6-ECDCA increased liver expression of Shp, bsep, multidrug resistance-associated protein-2, and multidrug resistance protein-2, whereas it reduced cyp7a1 and cyp8b1 and ntcp mRNA. These changes were reproduced by GW4064, a synthetic FXR ligand. In conclusion, by demonstrating that 6-ECDCA protects against E(2)17alpha cholestasis, our data support the notion that development of potent FXR ligands might represent a new approach for the treatment of cholestatic disorders.

Topics: Animals; Chenodeoxycholic Acid; Cholestasis; DNA-Binding Proteins; Dose-Response Relationship, Drug; Estrogens; Hepatocytes; Ligands; Male; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Transcription Factors

A series of 6alpha-alkyl-substituted analogues of chenodeoxycholic acid (CDCA) were synthesized and evaluated as potential farnesoid X receptor (FXR) ligands. Among them, 6alpha-ethyl-chenodeoxycholic acid (6-ECDCA) was shown to be a very potent and selective FXR agonist (EC(50) = 99 nM) and to be endowed with anticholeretic activity in an in vivo rat model of cholestasis.

Topics: Animals; Anticholesteremic Agents; Cell Line; Chenodeoxycholic Acid; Cholestasis; DNA-Binding Proteins; Humans; Ligands; Liver; Rats; Rats, Wistar; Receptors, Cytoplasmic and Nuclear; Structure-Activity Relationship; Transcription Factors