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Estrogen-induced intrahepatic cholestasis (IHC) is a mild but potentially serious risk and urges for new therapeutic targets and effective treatment. Our previous study demonstrated that RORγt and CXCR3 signaling pathway of invariant natural killer T (iNKT) 17 cells play pathogenic roles in 17α-ethinylestradiol (EE)-induced IHC. Ursodeoxycholic acid (UDCA) and 18β-glycyrrhetinic acid (GA) present a protective effect on IHC partially due to their immunomodulatory properties. Hence in present study, we aim to investigate the effectiveness of UDCA and 18β-GA in vitro and verify the accessibility of the above targets. Biochemical index measurement indicated that UDCA and 18β-GA presented efficacy to alleviate EE-induced cholestatic cytotoxicity. Both UDCA and 18β-GA exhibited suppression on the CXCL9/10-CXCR3 axis, and significantly restrained the expression of RORγt in vitro. In conclusion, our observations provide new therapeutic targets of UDCA and 18β-GA, and 18β-GA as an alternative treatment for EE-induced cholestasis., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024. Published by Elsevier Ltd.)

Hepatic cholestasis can develop into liver fibrosis and eventually liver failure. Currently, ursodeoxycholic acid (UDCA) or UDCA combined with fenofibrate is used for cholestasis treatment. Rosiglitazone inhibited α-naphthyl isothiocyanate (ANIT)-induced cholestasis in mice. In this study, we compared the effect of rosiglitazone, UDCA, fenofibrate, combined rosiglitazone and fenofibrate or UDCA and fenofibrate on ANIT-induced cholestasis. C57BL/6J mice were induced cholestasis by ANIT while treated with rosiglitazone, UDCA, fenofibrate, combination of rosiglitazone and fenofibrate, or combination of UDCA and fenofibrate. Liver and serum samples were collected to determine liver necrosis and serum biochemical parameters. Rosiglitazone alone or combined with fenofibrate demonstrated better effects than UDCA alone or UDCA combined with fenofibrate in reduction of cholestasis-induced serum biochemical parameters and liver necrosis. Surprisingly, UDCA combined with fenofibrate, but not rosiglitazone combined with fenofibrate, potently increased accumulation of free fatty acids (FFAs) in the liver. Mechanistically, the protection of combination of rosiglitazone and fenofibrate against cholestasis was attributed to activated adiponectin pathway to enhance FXR and mitochondrial functions and reduce apoptosis in the liver. The accumulation of FFAs in the liver by combination of UDCA and fenofibrate was caused by activation of fatty acid biosynthesis and uptake, and triglyceride hydrolysis. Taken together, our study not only demonstrates the adverse effect of combination therapy of UDCA and fenofibrate, but also suggests the combination of rosiglitazone and fenofibrate can be another option for cholestasis treatment., Competing Interests: Declaration of competing interest The authors declare that there are no competing interests associated with the manuscript., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Autophagy is a "housekeeping" lysosomal degradation process involved in numerous physiological and pathological processes in all eukaryotic cells. The dysregulation of hepatic autophagy has been described in several conditions, from obesity to diabetes and cholestatic disease. We review the role of autophagy, focusing on age-related cholestatic diseases, and discuss its therapeutic potential and the molecular targets identified to date. The accumulation of toxic BAs is the main cause of cell damage in cholestasis patients. BAs and their receptor, FXR, have been implicated in the regulation of hepatic autophagy. The mechanisms by which cholestasis induces liver damage include mitochondrial dysfunction, oxidative stress and ER stress, which lead to cell death and ultimately to liver fibrosis as a compensatory mechanism to reduce the damage. The stimulation of autophagy seems to ameliorate the liver damage. Autophagic activity decreases with age in several species, whereas its basic extends lifespan in animals, suggesting that it is one of the convergent mechanisms of several longevity pathways. No strategies aimed at inducing autophagy have yet been tested in cholestasis patients. However, its stimulation can be viewed as a novel therapeutic strategy that may reduce ageing-dependent liver deterioration and also mitigate hepatic steatosis.

Background & Aims: Gamma-glutamyltransferase (GGT) is a serum marker of cholestasis. We investigated whether serum level of GGT is a prognostic marker for patients with primary biliary cholangitis (PBC)., Methods: We analyzed data from patients with PBC from the Global PBC Study Group, comprising 14 centers in Europe and North America. We obtained measurements of serum GGT at baseline and time points after treatment. We used Cox model hazard ratios to evaluate the association between GGT and clinical outcomes, including liver transplantation and liver-related death., Results: Of the 2129 patients included in our analysis, 281 (13%) had a liver-related clinical endpoint. Mean age at diagnosis was 53 years and 91% of patients were female patients. We found a correlation between serum levels of GGT and alkaline phosphatase (ALP) (r = 0.71). Based on data collected at baseline and yearly for up to 5 years, higher serum levels of GGT were associated with lower hazard for transplant-free survival. Serum level of GGT at 12 months after treatment higher than 3.2-fold the upper limit of normal (ULN) identified patients who required liver transplantation or with liver-related death at 10 years with an area under the receiver operating characteristic curve of 0.70. The risk of liver transplantation or liver-related death in patients with serum level of GGT above 3.2-fold the ULN, despite level of ALP lower than 1.5-fold the ULN, was higher compared to patients with level of GGT lower than 3.2-fold the ULN and level of ALP lower than 1.5-fold the ULN (P < .05). Including information on level of GGT increased the prognostic value of the Globe score., Conclusions: Serum level of GGT can be used to identify patients with PBC at risk for liver transplantation or death, and increase the prognostic value of ALP measurement. Our findings support the use of GGT as primary clinical endpoint in clinical trials. In patients with low serum level of ALP, a high level of GGT identifies those who might require treatment of metabolic disorders or PBC treatment escalation., (Copyright © 2021 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Autophagy is a lysosomal degradation pathway in which the cell self-digests its own components to provide nutrients in harsh environmental conditions. It also represents an opportunity to rid the cell of superfluous and damaged organelles, misfolded proteins or invaded microorganisms. Liver autophagy contributes to basic hepatic functions such as lipid, glycogen and protein turnover. Deregulated hepatic autophagy has been linked to many liver diseases including alpha-1-antitrypsin deficiency, alcoholic and non-alcoholic fatty liver diseases, hepatitis B and C infections, liver fibrosis as well as liver cancer. Recently, bile acids and the bile acid receptor FXR have been implicated in the regulation of hepatic autophagy, which implies a role of autophagy also for cholestatic liver diseases. This review summarizes the current evidence of bile acid mediated effects on autophagy and how this affects cholestatic liver diseases. Although detailed studies are lacking, we suggest a concept that the activity of autophagy in cholestasis depends on the disease stage, where autophagy may be induced at early stages ("cholestophagy") but may be impaired in prolonged cholestatic states ("cholestopagy")., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Estrogen-induced cholestasis, known as intrahepatic cholestasis of pregnancy (ICP), is an estrogen-related liver disease that is widely recognized as female or pregnancy-specific. Our previous findings showed that the synthetic estrogen, 17α-ethinylestradiol (EE), induced cholestatic injury through ERK1/2-LKB1-AMP-activated protein kinase (AMPK) signaling pathway and its mediated suppression of farnesoid X receptor (FXR). To investigate the role played by bile acids in EE-induced cholestasis, we evaluated the effects of chenodeoxycholic acid (CDCA), ursodeoxycholic acid (UDCA) and deoxycholic acid (DCA) on sandwich cultured rat primary hepatocytes (SCRHs) and an in vivo rat model. Our results showed that, both CDCA and UDCA significantly induced time- and concentration-dependent reduction in AMPK phosphorylation in SCRHs. Despite having different effects on FXR activation, CDCA and UDCA both inhibited EE-induced AMPK activation, accompanied with the up-regulation of FXR and its downstream bile acid transporters. However, although DCA activates FXR and induces SHP, it was unable to alleviate EE-induced FXR suppression and further aggravated EE-induced cholestasis. We further demonstrated that both CDCA and UDCA, but not DCA, activated cyclic AMP dependent protein kinase (PKA) in SCRHs and the livers of male rats (8weeks old) liver. Furthermore, PKA antagonist, H89, blocked the AMPK inhibition by CDCA and UDCA, and pharmacological and genetic activation of PKA suppressed EE-induced AMPK activation and its downstream effects. Collectively, these results suggest that CDCA and UDCA protect against estrogen-induced cholestatic injury via PKA signaling pathway and up-regulation of EE-suppressed FXR, which suggests a potential therapeutic target for ICP., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Ursodeoxycholic acid (UDCA) is the first-line treatment for primary biliary cholangitis (PBC), but 20–40% of patients do not respond well to UDCA. We aimed to develop and validate a prognostic model for the early prediction of patients who nonresponse to UDCA. This retrospective analysis was conducted among patients with primary biliary cholangitis(N = 257) to develop a predictive model for early-stage nonresponse to ursodeoxycholic acid (UDCA) therapy. The model's reliability was subsequently confirmed through external validation in an independent cohort(N = 71). Multivariate cox regression analysis was used to evaluate variables that were significant in the univariate analysis. Total cholesterol, alkaline phosphatase (ALP), and neutrophil-to-lymphocyte ratio (NLR) were the three independent risk factors associated with early biochemical nonresponse to UDCA treatment. Based on these factors, we established a predictive model that possessed good discriminative ability, as reflected by an AUC of 0.862(95%CI = 0.813–0.911). The ROC curve of the external validation set calculated the AUC of 0.916(95%CI:0.823–1.000). In summary, we developed an early predictive model that could identify potential nonresponse factors to UDCA at baseline, which could facilitate risk evaluation and stratification for PBC patients. The NLR and total cholesterol provided a supplementary means for effectively managing PBC patients. [ABSTRACT FROM AUTHOR]

Magd A Kotb,1 Iman Draz,1 Christine WS Basanti,1 Sally TM El Sorogy,2 Hesham M Abd Elkader,3 Haytham Esmat,4 Hend Abd El Baky,1 Dalia Sayed Mosallam1 1Pediatrics Department, Faculty of Medicine, Kasr Al Ainy, Cairo University, Cairo, Egypt; 2Pediatrics Department, Public Mounira Hospital, Cairo, Egypt; 3Department of Pediatric Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt; 4Department of Pediatric Surgery, Cairo University, Cairo, EgyptCorrespondence: Dalia Sayed MosallamPediatrics Department, Faculty of Medicine, Cairo University, Al Manial, Cairo 11562, EgyptTel +20 2 33386592Email daliamosalam@kasralainy.edu.egPurpose: We aimed to define the clinical presentations, course and outcome of cholestasis in infants with Down syndrome (trisomy 21) who presented to the Pediatric Hepatology Clinic, New Children Hospital, Cairo University, Egypt.Methods: Retrospective analysis of data of cohort of infants with Down syndrome and cholestasis who followed up during 2005–2015.Results: Among 779 infants with cholestasis who presented during 2005–2015, 61 (7.8%) had Down syndrome. Six dropped out. Among the 55 who followed-up for a mean duration +SD = 12.1 ± 16.7 months, none had extrahepatic biliary atresia (EHBA), 37 (63.3%) had neonatal hepatitis and 18 (32.7%) had non-syndromic paucity of intrahepatic biliary radicals. Fourteen (25.4%) had associated congenital heart disease. Only 35 (63.3%) cleared the jaundice. Twenty-nine (52.7%) received ursodeoxycholic acid (UDCA); of them, 13 cleared the jaundice, one improved, 14 progressed and one died, compared to 22 who cleared the jaundice of the 26 who did not receive UDCA. Only three of those who did not receive UDCA progressed and none died. UDCA carried a 3.4-fold risk of poor prognosis (p= 0.001). UDCA use was associated with more complications (p= 0.016) in those with Down syndrome and cholestasis.Conclusion: We did not come across EHBA among neonates and infants with Down syndrome in 10 years. Non-syndromic paucity is associated with favorable outcome in infants with Down syndrome. UDCA use in cholestasis with Down syndrome is associated with poor outcome.Keywords: cholestasis, extrahepatic biliary atresia, EHBA, neonatal hepatitis, Down syndrome, trisomy 21, ursodeoxycholic acid, UDCA

Purpose of Review: The purpose of this review is to discuss reasons why immunosuppressive therapy so far failed in Primary Biliry Cholangitis. Recent Findings: Even targeted immunosuppressive therapy seems ineffective or potentially harmful. Summary: Bile acid-mediated cholangiocyte damage, facilitated by insufficient bicarbonate secretion, seems to attenuate the anti-inflammatory and anti-fibrotic actions of immunosuppressant and immunomodulatory drugs in a clinically significant way. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis (PSC) is a major unmet medical need in clinical hepatology. Cilofexor is a nonsteroidal farnesoid X receptor agonist being evaluated for the treatment of PSC. Here, we describe the safety and preliminary efficacy of cilofexor in a 96-week, open-label extension (OLE) of a phase II trial. Noncirrhotic subjects with large-duct PSC who completed the 12-week, blinded phase of a phase II study (NCT02943460) were eligible, after a 4-week washout period, for a 96-week OLE with cilofexor 100 mg daily. Safety, liver biochemistry, and serum markers of fibrosis, cellular injury, and pharmacodynamic effects of cilofexor (fibroblast growth factor 19, C4, and bile acids [BAs]) were evaluated. Among 52 subjects enrolled in the phase II study, 47 (90%) continued in the OLE phase (median age, 44 years; 60% male patients, 60% with inflammatory bowel disease, and 45% on ursodeoxycholic acid [UDCA]). At OLE baseline (BL), the median serum alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) were 368 U/L (interquartile range [IQR], 277–468 U/L) and 417 U/L (IQR, 196–801 U/L), respectively. Of the 47 subjects enrolled, 15 (32%) discontinued treatment prematurely (pruritus [n = 5], other adverse events [n = 5], subject decision/investigator discretion [n = 5]). At week 96, reductions in liver biochemistry parameters occurred, including serum ALP (median, −8.3% [IQR, −25.9% to 11.0%]; P =.066), GGT (−29.8% [IQR, −42.3% to −13.9%]; P <.001), alanine aminotransaminase (ALT) (−29.8% [IQR, −43.7% to −6.6%]; P =.002), and aspartate aminotransaminase (AST) (−16.7% [IQR, −35.3% to 1.0%]; P =.010), and rebounded after 4 weeks of untreated follow-up. ALP response (≥20% reduction from BL to week 96) was similar in the presence or absence of UDCA therapy (29% vs 39%; P =.71). At week 96, cilofexor treatment was associated with a significant reduction in serum 7α-hydroxy-4-cholesten-3-one (C4) (−29.8% [IQR, −64.3% to −8.5%]; P =.001). In subjects with detectable serum BAs at BL (n = 40), BAs decreased −23.9% (IQR, −44.4% to −0.6%; P =.006) at week 48 (n = 28) and −25.7% (IQR, −35.9% to 53.7%; P =.91) at week 96 (n = 26). Serum cytokeratin 18 (CK18) M30 and M65 were reduced throughout the OLE; significant reductions were observed at week 72 (CK18 M30, −17.3% [IQR, −39.3% to 8.8%]; P =.018; CK18 M65, −43.5% [IQR, −54.9% to 15.3%]; P =.096). At week 96, a small, but statistically significant absolute increase of 0.15 units in Enhanced Liver Fibrosis score was observed compared with BL (median, 9.34 vs 9.53; P =.028). In this 96-week OLE of a phase II study of PSC, cilofexor was safe and improved liver biochemistry and biomarkers of cholestasis and cellular injury. ClinicalTrials.gov identifier: NCT02943460 [ABSTRACT FROM AUTHOR]

Background & Aims: The quest for effective drugs to treat cholangiopathies led to the development of norUDCA previously shown to have potent choleretic effects and to heal cholangiopathy in Abcb4 knockout (Abcb4 −/−) mice. Its mother compound UDCA had detrimental effects in common bile duct ligated (CBDL) mice, presumably related to its choleretic effects. norUDCA choleretic effects may therefore raise safety concerns when used in cholangiopathies with biliary obstruction. We therefore aimed at comparing the effects of UDCA and norUDCA in clear-cut obstructive cholestasis. Methods: 0.5% UDCA- or norUDCA-fed wild type and Abcb4 −/− mice were subjected to CBDL or selective bile duct ligation (SBDL) and compared to controls with regard to liver injury. Bile flow, bile composition, and biliary manometry were compared in UDCA-fed, norUDCA-fed and control mice. Toxicity of UDCA and norUDCA was compared in vitro. Results: Compared to UDCA, liver injury in CBDL mice was significantly lower in almost all norUDCA groups. In SBDL mice, only UDCA induced bile infarcts in the ligated lobes, whereas norUDCA even ameliorated liver injury. In vitro, UDCA induced cellular ATP depletion and was significantly more toxic than norUDCA in HepG2 cells, mouse bile duct epithelial cells, and primary human hepatocytes. Conclusions: Compared to norUDCA, UDCA is significantly more toxic in CBDL mice. norUDCA, in contrast to UDCA, significantly ameliorates liver injury in SBDL mice. Our findings uncover profound differences in metabolism and therapeutic mechanisms of both bile acids with important clinical consequences. [ABSTRACT FROM AUTHOR]

Primary sclerosing cholangitis (PSC) is a rare cholestatic liver disease mainly affecting young male patients. PSC is characterised by chronic inflammation and fibrotic strictures of the intra- and extrahepatic biliary system, which eventually lead to cholestasis and biliary cirrhosis. However, the clinical course remains very variable. As the aetiology remains unknown, the development of a causative treatment is challenging and today no specific medical therapy is available. Ursodeoxycholic acid has been widely used for the treatment of PSC, but improved only biochemistry and/or symptoms in low- or medium dosages and is probably harmful in higher dosages. Other drugs such as immunosuppressive, antifibrotic or antibiotic agents have not been proven to be effective in large clinical trials. The endoscopic therapy encompasses balloon-dilatation and/or stenting of strictures, relieves clinical symptoms and improves a cholestatic enzyme profile. However, endoscopic therapy is limited to patients in advanced stages of PSC with biliary obstruction. [Copyright &y& Elsevier]

We retrospectively reviewed the role of ursodeoxycholic acid in infants having nonsurgical cholestasis attending the Hepatology Clinic, New Children Hospital, Cairo University, Egypt, from 1985 until 2005. Files of 496 infants with neonatal hepatitis and 97 with intrahepatic bile duct paucity were included; of them 241 (48.6%) and 52 (46.4%) received 20-40 mg/kg/day ursodeoxycholic acid for 319.2 +/- 506.9 days and 480.3 +/- 583.3 days, respectively. The outcome of infants with neonatal hepatitis with intake of ursodeoxycholic acid and those without was: 108 (44.8%) and 179 (70.2%) successful (P = 0.000), 11 (4.6%) and 13 (5.1%) improved (P = 0. 474), 112 (46.5%) and 61 (23.9%) suffered failed outcome (P = 0.000), and 10 (4.1%) and 2 (0.78%) died (P = 0.014), respectively. Likelihood of successful outcome with ursodeoxycholic acid intake was 0.345 (P = 0.000), and that of deterioration was 2.76 (P = 0.000). For those having intrahepatic bile duct paucity likelihood of successful outcome with ursodeoxycholic acid intake was 0.418 (P = 0.040) and that of deterioration was 2.64 (P = 0.028). Ursodeoxycholic acid failed in management of this cohort of infants with nonsurgical cholestasis. [ABSTRACT FROM AUTHOR]

Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease with a slowly progressive course. Without treatment, most patients eventually develop fibrosis and cirrhosis of the liver and may need liver transplantation in the late stage of disease. PBC primarily affects women (female preponderance 9–10:1) with a prevalence of up to 1 in 1,000 women over 40 years of age. Common symptoms of the disease are fatigue and pruritus, but most patients are asymptomatic at first presentation. The diagnosis is based on sustained elevation of serum markers of cholestasis, i.e., alkaline phosphatase and gamma-glutamyl transferase, and the presence of serum antimitochondrial antibodies directed against the E2 subunit of the pyruvate dehydrogenase complex. Histologically, PBC is characterized by florid bile duct lesions with damage to biliary epithelial cells, an often dense portal inflammatory infiltrate and progressive loss of small intrahepatic bile ducts. Although the insight into pathogenetic aspects of PBC has grown enormously during the recent decade and numerous genetic, environmental, and infectious factors have been disclosed which may contribute to the development of PBC, the precise pathogenesis remains enigmatic. Ursodeoxycholic acid (UDCA) is currently the only FDA-approved medical treatment for PBC. When administered at adequate doses of 13–15 mg/kg/day, up to two out of three patients with PBC may have a normal life expectancy without additional therapeutic measures. The mode of action of UDCA is still under discussion, but stimulation of impaired hepatocellular and cholangiocellular secretion, detoxification of bile, and antiapoptotic effects may represent key mechanisms. One out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy and/or liver transplantation. This review summarizes current knowledge on the clinical, diagnostic, pathogenetic, and therapeutic aspects of PBC. [ABSTRACT FROM AUTHOR]

Abstract: 3α-6α-Dihydroxy-7α-fluoro-5β-cholanoate (UPF-680), the 7α-fluorine analog of hyodeoxycholic acid (HDCA), was synthesized to improve bioavailability and stability of ursodeoxycholic acid (UDCA). Acute rat biliary fistula and chronic cholestasis induced by 17α-ethynyl-estradiol (17EE) models were used to study and compare the effects of UPF-680 (dose range 0.6–6.0 μmol/kg min) with UDCA on bile flow, biliary bicarbonate (HCO3 −), lipid output, biliary bile acid composition, hepatic enzymes and organic anion pumps. In acute infusion, UPF-680 increased bile flow in a dose-related manner, by up to 40.9%. Biliary HCO3 − output was similarly increased. Changes were observed in phospholipid secretion only at the highest doses. Treatment with UDCA and UPF-680 reversed chronic cholestasis induced by 17EE; in this model, UDCA had no effect on bile flow in contrast to UPF-680, which significantly increased bile flow. With acute administration of UPF-680, the biliary bile acid pool became enriched with unconjugated and conjugated UPF-680 (71.7%) at the expense of endogenous cholic acid and muricholic isomers. With chronic administration of UPF-680 or UDCA, the main biliary bile acids were tauro conjugates, but modification of biliary bile acid pool was greater with UPF-680. UPF-680 increased the mRNA for cytochrome P450 7A1 (CYP7A1) and cytochrome P450 8B (CYP8B). Both UDCA and UPF-680 increased the mRNA for Na+ taurocholate co-transporting polypeptide (NCTP). In conclusion, UPF-680 prevented 17EE-induced cholestasis and enriched the biliary bile acid pool with less detergent and cytotoxic bile acids. This novel fluorinated bile acid may have potential in the treatment of cholestatic liver disease. [Copyright &y& Elsevier]

A five month old child with biliary atresia and cholestasis was treated with acupuncture, ursodeoxycholic acid, naturopathy and Chinese herbal medicine with a positive outcome. [ABSTRACT FROM AUTHOR]

Hepatic graft-versus-host disease (GVHD) is a frequent complication after bone-marrow transplantation (BMT). The disease is often refractory to immunosuppressive therapy. We present a 30-year-old Japanese male, who developed an abrupt elevation of aminotransferases, on day 135 after allogeneic BMT. A liver biopsy specimen revealed degeneration of the small bile ducts and portal fibrosis, and the diagnosis of chronic hepatic GVHD was confirmed. No manifestation of chronic GVHD was observed except liver dysfunction. The administration of prednisolone (PSL) and cyclosporin (CsA) ameliorated laboratory data to a degree, but they did not return to normal. Treatment with ursodeoxycholic acid (UDCA), subsequently added to the immunosuppressive therapy, apparently normalized the levels of biliary tract enzyme and total bilirubin. His liver function test completely returned to normal on day 260. We believe that it is worthwhile to administer UDCA as an additional treatment for not only common hepatic GVHD but also atypical cases presenting as acute hepatitis. [ABSTRACT FROM AUTHOR]

The article discusses the use of ursodeoxycholic acid (UDCA) for the treatment of primary sclerosing cholangitis (PSC), a rare and chronic cholestatic liver disease associated with inflammatory bowel disease (IBD). Topics discussed include the lack of proven survival benefits in patients and the lack of one methylene group in the side chain of UDCA which confers a relative resistance to amidation.

Summary Cholestasis is an impairment of bile formation/flow at the level of the hepatocyte and/or cholangiocyte. The first, and for the moment, most established medical treatment is the natural bile acid (BA) ursodeoxycholic acid (UDCA). This secretagogue improves, e.g. in intrahepatic cholestasis of pregnancy or early stage primary biliary cirrhosis, impaired hepatocellular and cholangiocellular bile formation mainly by complex post-transcriptional mechanisms. The limited efficacy of UDCA in various cholestatic conditions urges for development of novel therapeutic approaches. These include nuclear and membrane receptor agonists and BA derivatives. The nuclear receptors farnesoid X receptor (FXR), retinoid X receptor (RXR), peroxisome proliferator-activated receptor α (PPARα), and pregnane X receptor (PXR) are transcriptional modifiers of bile formation and at present are under investigation as promising targets for therapeutic interventions in cholestatic disorders. The membrane receptors fibroblast growth factor receptor 4 (FGFR4) and apical sodium BA transporter (ASBT) deserve attention as additional therapeutic targets, as does the potential therapeutic agent nor UDCA, a 23-C homologue of UDCA. Here, we provide an overview on established and future promising therapeutic agents and their potential molecular mechanisms and sites of action in cholestatic diseases. [ABSTRACT FROM AUTHOR]