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Increased hepatoprotective effects of the novel farnesoid X receptor agonist INT-787 versus obeticholic acid in a mouse model of nonalcoholic steatohepatitis

ABSTRACT: We applied RNA sequencing to study the hepatic gene expression profile of Lep(ob/ob) mice fed the Amylin liver NASH (AMLN) diet for 14 weeks and then treated for 2 weeks with vehicle (n=10), obeticholic acid (OCA) (n=9), or INT-787 (n=9). INT-787, which is equipotent to OCA but more hydrophilic, modulated a substantially greater number of genes associated with FXR signaling, lipid metabolism, and stellate cell activation relative to OCA.

ORGANISM(S): Mus musculus

PROVIDER: GSE263273 | GEO | 2024/04/11

REPOSITORIES: GEO

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Gene expression profiling and TF occupancy upon treatment with the FXR agonist obeticholic acid

Project description:The farnesoid X receptor (FXR) is a nuclear receptor activated by bile acids and regulates bile acid metabolism, glucose and cholesterol homeostasis. From mouse studies we know that the novel FXR agonist obeticholic acid (OCA) regulates expression of many genes in the liver, but there is currently no data on the effects of OCA on human liver gene expression. This is especially relevant since the novel FXR agonist OCA is currently tested in clinical trials for the treatment of several diseases, such as nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD) and Type 2 Diabetes. In this study we investigate the effect of OCA treatment on gene expression profiles and localization of FXR to the genome in relevant liver samples. ChIP-Seq for FXR in Liver tissue from 2 male mice treated with OCA/INT-747 (10mg/kg/day) and 2 male mice treated with vehicle (1% methyl cellulose).

2016-01-27 | E-GEOD-73624 | biostudies-arrayexpress

Gene expression profiling in human precision-cut liver slices upon treatment with the FXR agonist obeticholic acid [mouse]

Project description:Background: The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA; also known as INT-747 or 6α-ethyl-chenodeoxycholic acid), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH) and type 2 diabetes, activates FXR. Mouse studies demonstrated that FXR activation by OCA (INT-747) alters hepatic expression of many genes. However, no data are available on the effects of OCA in human liver. Here, we generated gene expression profiles in human precision-cut liver slices (hPCLS) after treatment with OCA. Methods: hPCLS were incubated with OCA for 24 h. WT or FXR -/- mice received OCA or vehicle by oral gavage for 7 days. Results: Transcriptomic analysis showed that well-known FXR target genes, including NR0B2 (SHP), ABCB11 (BSEP), SLC51A (OSTα) and SLC51B (OSTβ) and ABCB4 (MDR3), are regulated by OCA in hPCLS. Ingenuity pathway analysis confirmed that 'FXR/RXR activation' is the most significantly changed pathway upon OCA treatment. Comparison of gene expression profiles in hPCLS and mouse livers identified 18 common potential FXR targets. ChIP-sequencing in mouse liver confirmed FXR binding to IR1 sequences of Akap13, Cgnl1, Dyrk3, Pdia5, PPP1R3B and Tbx6. Conclusions: Our study shows that hPCLS respond to OCA treatment by upregulating well-known FXR target genes, demonstrating its suitability to study FXR-mediated gene regulation. We identified 6 novel bona-fide FXR target genes in both mouse and human liver. Finally, we discuss a possible explanation for changes in HDL/LDL observed in NASH and primary biliary cirrhosis patients treated with OCA based on the genomic expression profile in hPCLS.

2016-01-27 | GSE76162 | GEO

Gene expression profiling in human precision-cut liver slices upon treatment with the FXR agonist obeticholic acid [human]

2016-01-27 | GSE76161 | GEO

Increased hepatoprotective effects of the novel farnesoid X receptor agonist INT-787 versus obeticholic acid in a mouse model of nonalcoholic steatohepatitis

Project description:Increased hepatoprotective effects of the novel farnesoid X receptor agonist INT-787 versus obeticholic acid in a mouse model of nonalcoholic steatohepatitis

| PRJNA1096425 | ENA

Gene expression profiling and TF occupancy upon treatment with the FXR agonist obeticholic acid

2016-01-27 | GSE73624 | GEO

Testing Obeticholic Acid for Familial Adenomatous Polyposis

Project description:This phase IIa trial investigates if giving obeticholic acid (OCA) is safe and has a beneficial effect on the number of polyps in the small bowel and colon in patients with familial adenomatous polyposis (FAP). FAP is a rare gene defect that increases the risk of developing cancer of the intestines and colon. OCA is a drug similar to a bile acid the body makes. It is fluid made and released by the liver. OCA binds to a receptor in the intestine that is believed to have a positive effect on preventing cancer development. OCA has been effective in treating primary biliary cholangitis (PBC), a liver disease, and is approved by the Food and Drug Administration (FDA) for use at a lower dose (10 mg). There have been studies showing that OCA decreases inflammation and fibrosis. However, it is not yet known whether OCA works on reducing the number of polyps in patients with FAP.

| 2403388 | ecrin-mdr-crc

Role of Farnesoid X Receptor (FXR) in Valproic acid-induced Hepatotoxicity

Project description:Drug-induced steatosis and steatohepatitis manifest clinically as nonalcoholic fatty liver disease (NAFLD). Drugs associated with steatosis include valproic acid (VPA). VPA has been one of the most widely used antiepileptic drugs over the past 40 years. However, clinical follow-up studies have reported that more than 40% of patients who received VPA also developed fatty liver disease. Steatosis is a typical clinical effect of VPA treatment and is characterized by an abnormal accumulation of lipids in liver cells. The aim of this study is to investigate whether activation of the farnesoid X receptor (FXR) by obeticholic acid (OCA), which is an effective agent in the treatment of NAFLD, can also prevent VPA-induced steatosis. OCA is a synthetic bile acid derivative that potently activates FXR and the FXR-regulated pathways that maintain bile acid, lipid and glucose homeostasis. Female C57BL/6 mice were fed a standard chow diet or chow containing OCA (dose 250 mg/kg body weight) for four weeks. Each group was then divided into two sub-groups: one co-treated with VPA (dose 100 mg/kg body weight) and another treated with the same volume of H2O by oral gavage daily for an additional four weeks. Mice liver were isolated and RNA isolated for RNA-Seq.

2020-05-01 | GSE138810 | GEO

Tropifexor-Mediated Abrogation of Steatohepatitis and Fibrosis Is Associated With Antioxidative Gene Expression Profile in Rodents

Project description:Farnesoid X receptor (FXR) agonism is emerging as an important potential therapeutic mechanism of action for multiple chronic liver diseases. The bile acid–derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in a phase 2 study in patients with nonalcoholic steatohepatitis (NASH). Here, we report efficacy of a novel, non–bile acid FXR agonist tropifexor (LJN452) in two distinct preclinical models of NASH. The efficacy of tropifexor at <1 mg/kg doses was superior to that of OCA at 25 mg/kg in the liver in both NASH models. In a chemical and dietary model of NASH (STAM model), tropifexor reversed established fibrosis and reduced nonalcoholic fatty liver disease activity score and hepatic triglycerides. In an insulin-resistant, obese NASH model (AMLN), tropifexor markedly reduced steatohepatitis, fibrosis, and profibrogenic gene expression. Transcriptome analysis of livers from AMLN mice revealed 461 differentially expressed genes following tropifexor treatment, which included a combination of signatures associated with reduction of oxidative stress, fibrogenesis, and inflammation. Conclusion: Based on the preclinical validation in animal models, tropifexor is a promising investigational therapy that is currently under phase 2 development for NASH.

2019-08-20 | GSE129389 | GEO

Project description:Obeticholic acid and ferrostatin-1 synergize to ameliorate nonalcoholic steatohepatitis in AMLN diet-fed ob/ob mice

| PRJNA884173 | ENA

Discovery biomarker to optimize obeticholic acid treatment for non-alcoholic fatty liver disease

Project description:To compare the gene expression of these groups before OCA treatment in responders with therapeutic effect on OCA and non-responders without therapeutic effect, mRNA-seq was performed on liver biopsy samples before OCA administration.

2022-10-13 | GSE215196 | GEO

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