Farsenoid X Receptor

Xanthohumol (XN) improves cognition of wild-type rodents on a high fat diet. Bile acids and ceramide levels in the liver and hippocampus might be linked to these effects. XN modulates activity of the nuclear farsenoid X receptor (FXR), the primary receptor family for bile acids. To determine the role of FXR in the liver and intestine in mediating the effects of XN on cognitive performance, mice with intestine- and liver-specific FXR-ablation (FXRIntestine-/- and FXRLiver-/-) on a HFD or a HFD containing XN were cognitively tested...

EDP-305 is a farnesoid X receptor (FXR) agonist that selectively activates FXR and is a potential treatment for patients with nonalcoholic steatohepatitis (NASH) with liver fibrosis. Results from preclinical studies indicate that CYP3A4 is the primary enzyme involved in EDP-305 metabolism and that EDP-305 has low potential to inhibit or induce cytochrome (CYP) isoenzymes and drug transporters. Four studies were conducted in healthy volunteers to evaluate the drug-drug interaction potential of EDP-305 coadministered with drugs known to be substrates for drug metabolizing enzymes or transporters, and to assess the effect of inhibitors and inducers of CYP3A4 on EDP-305...

BACKGROUND: Cerebrotendinous xanthomatosis (CTX) is a disorder of bile acid (BA) metabolism due to biallelic mutations in CYP27A1. The deposition of cholesterol and cholestanol in multiple tissues results, manifesting as neurologic disease in adults or older children. Neonatal cholestasis (NC) as a presentation of CTX is rare; it may self-resolve or persist, evolving to require liver transplantation (LT). METHODS: We present in the context of similar reports an instance of CTX manifest as NC and requiring LT...

OBJECTIVE: This study investigates the protective properties of farsenoid X receptor (FXR) agonism by the drug Obeticholic Acid (OCA) in the adenine-induced tubulointerstitial fibrosis model of kidney disease male and female mice. HYPOTHESIS: OCA treatment will decrease the expression of SMAD3 and phosphorylated-SMAD3, and therefore will be nephroprotective in the adenine model of kidney disease in male and female mice. METHODS: Male and female C57BL/6J mice (12 weeks old) were fed chow (Research Diets D1912040li) or chow admixed with adenine (0...

Bile acids (BAs) are the central signals in enterohepatic communication, and they also integrate microbiota-derived signals into enterohepatic signaling. The tissue distribution and signaling pathways activated by BAs through natural receptors, farsenoid X receptor and G protein-coupled BA receptor 1 (GPBAR1, also known as Takeda G-coupled receptor 5), have led to a greater understanding of the mechanisms and potential therapeutic agents. BA diarrhea is most commonly encountered in ileal resection or disease, in idiopathic disorders (with presentation similar to functional diarrhea or irritable bowel syndrome with diarrhea), and in association with malabsorption such as chronic pancreatitis or celiac disease...

PURPOSE OF REVIEW: This review will summarize the use of obeticholic acid (OCA) in treatment of primary biliary cholangitis (PBC). It seeks to discuss the mechanism of action, evidence for use, appropriate clinical use, and common adverse effects of OCA. RECENT FINDINGS: PBC is a chronic, progressive cholestatic liver disease that is a chronic progressive that may lead to end-stage liver disease and need for liver transplantation. Ursodeoxycholic acid (UDCA) has been the mainstay of therapy for PBC for decades...

Chronic renal disease (CRD) associated with cardiovascular disease (CVD) and/or type 2 diabetes (T2D) is a significant problem in Aboriginal Australians. Whole exome sequencing data (N = 72) showed enrichment for ClinVar pathogenic variants in gene sets/pathways linking lipoprotein, lipid and glucose metabolism. The top Ingenuity Pathway Analysis canonical pathways were Farsenoid X Receptor and Retinoid Receptor (FXR/RXR; (P = 1.86 × 10-7 ), Liver X Receptor and Retinoid Receptor (LXR/RXR; P = 2...

Farnesoid X receptor (FXR) is a nuclear receptor related to lipid and glucose homeostasis and is considered an important molecular target to treatment of metabolic diseases as diabetes, dyslipidemia, and liver cancer. Nowadays, there are several FXR agonists reported in the literature and some of it in clinical trials for liver disorders. Herein, a compound series was employed to generate QSAR models to better understand the structural basis for FXR activation by anthranilic acid derivatives (AADs). Furthermore, here we evaluate the inclusion of the standard deviation (SD) of EC50 values in QSAR models quality...

The gut microbiome plays an important role in health and disease. Antibiotics are known to alter gut microbiota, yet their effects on glucose tolerance in lean, normoglycemic mice have not been widely investigated. In this study, we aimed to explore mechanisms by which treatment of lean mice with antibiotics (ampicillin, metronidazole, neomycin, vancomycin, or their cocktail) influences the microbiome and glucose metabolism. Specifically, we sought to: (i) study the effects on body weight, fasting glucose, glucose tolerance, and fasting insulin, (ii) examine the changes in expression of key genes of the bile acid and glucose metabolic pathways in the liver and ileum, (iii) identify the shifts in the cecal microbiota, and (iv) infer interactions between gene expression, microbiome, and the metabolic parameters...

The Drug Design Data Resource (D3R) consortium organises blinded challenges to address the latest advances in computational methods for ligand pose prediction, affinity ranking, and free energy calculations. Within the context of the second D3R Grand Challenge several blinded binding free energies predictions were made for two congeneric series of Farsenoid X Receptor (FXR) inhibitors with a semi-automated alchemical free energy calculation workflow featuring FESetup and SOMD software tools. Reasonable performance was observed in retrospective analyses of literature datasets...

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INTRODUCTION: Cholestasis is characterized by accumulation of bile acids and inflammation, causing hepatocellular damage. Still, liver damage markers are highest in acute cholestasis and drop when this condition becomes chronic, indicating that hepatocytes adapt towards the hostile environment. This may be explained by a hormetic response in hepatocytes that limits cell death during cholestasis. AIM: To investigate the mechanisms that underlie the hormetic response that protect hepatocytes against experimental cholestatic conditions...

Lifestyle modifications and optimization of the management of cardiometabolic comorbidities are currently the mainstay of treatment for patients with nonalcoholic fatty liver disease. Pharmacotherapy to halt or reverse hepatic histological injury and prevent the development of end-stage liver disease is specifically offered to patients with nonalcoholic steatohepatitis (NASH) and those with advanced fibrosis. In this review, the authors discuss the state of the art of various pharmacological agents for NASH...

Non-alcoholic fatty liver disease (NAFLD) is a major health care problem and represents the hepatic expression of the metabolic syndrome. NAFLD is classified as non-alcoholic fatty liver (NAFL) or simple steatosis, and non-alcoholic steatohepatitis (NASH). NASH is characterized by the presence of steatosis and inflammation with or without fibrosis. The physiopathology of NAFL and NASH and their progression to cirrhosis involve several parallel and interrelated mechanisms, such as, insulin resistance (IR), lipotoxicity, inflammation, oxidative stress, and recently the gut-liver axis interaction has been described...

BACKGROUND & AIMS: Liver regeneration (LR) is a valuable model for studying mechanisms modulating hepatocyte proliferation. Nuclear receptors (NRs) are key players in the control of cellular functions, being ideal modulators of hepatic proliferation and carcinogenesis. METHODS & RESULTS: We used a previously validated RT-qPCR platform to profile modifications in the expression of all 49 members of the NR superfamily in mouse liver during LR. Twenty-nine NR transcripts were significantly modified in their expression during LR, including fatty acid (peroxisome proliferator-activated receptors, PPARs) and oxysterol (liver X receptors, Lxrs) sensors, circadian masters RevErbα and RevErbβ, glucocorticoid receptor (Gr) and constitutive androxane receptor (Car)...

Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targets for therapeutic intervention. Substantial changes in circulating total bile acids are known to occur after VSG. Moreover, bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4)...

Probiotic microorganisms have been documented over the past two decades to play a role in cholesterol-lowering properties via various clinical trials. Several mechanisms have also been proposed and the ability of these microorganisms to deconjugate bile via production of bile salt hydrolase (BSH) has been widely associated with their cholesterol lowering potentials in prevention of hypercholesterolemia. Deconjugated bile salts are more hydrophobic than their conjugated counterparts, thus are less reabsorbed through the intestines resulting in higher excretion into the feces...

PURPOSE OF REVIEW: This review focuses on the recent advances in cholestatic liver diseases. While there is an emphasis placed on translational and treatment-focused studies, basic science studies with the greatest impact on the field are also covered. RECENT FINDINGS: Highlights include new discoveries for the role of the farsenoid X receptor and sodium-dependent taurocholate cotransporting polypeptide; new insights into the pathogenesis of progressive familial intrahepatic cholestasis type 1, biliary atresia, intrahepatic cholestasis of pregnancy, and primary biliary cirrhosis; new information for assessing prognosis in biliary atresia and primary biliary cirrhosis; and important clinical trials in intrahepatic cholestasis of pregnancy, primary biliary cirrhosis and primary sclerosing cholangitis...

Conversion of cholesterol to bile acids in the liver is initiated by the rate-limiting enzyme cholesterol 7alpha-hydroxylase (CYP7A1) and excretion of bile acids from the liver is mediated by the bile salt export pump (BSEP). The expression of CYP7A1 and BSEP is coordinately regulated by a negative feedback and positive feed-forward mechanism, respectively, through bile acid-mediated activation of farsenoid X receptor (FXR). It is well established that hypolipidemic agent guggulsterone is an FXR antagonist and down-regulates FXR target genes...

PURPOSE OF REVIEW: This review highlights recent advances in understanding the regulation of bile acid transport in cholestasis and in the pathogenesis, outcomes, epidemiology, and treatment of a variety of cholestatic liver diseases and their associated complications. RECENT FINDINGS: Highlights include additional understanding of the role of the nuclear receptors farsenoid X receptor, pregnane X receptor, and constitutive androstane receptor in bile acid homeostasis, new understanding of the pathogenesis of primary biliary cirrhosis, familial intrahepatic cholestasis, biliary atresia, and primary sclerosing cholangitis, and clinical trials of therapies for intrahepatic cholestasis of pregnancy, primary biliary cirrhosis, and primary sclerosing cholangitis...