obeticholic-acid and Carcinoma--Hepatocellular

Topics: Adolescent; Asia; Bariatric Surgery; Carcinoma, Hepatocellular; Chenodeoxycholic Acid; Child; Diet; Exercise; Fatty Acids, Omega-3; Gastroenterology; Humans; Liver Neoplasms; Liver Transplantation; Non-alcoholic Fatty Liver Disease; Obesity; Pacific Islands; Practice Guidelines as Topic; Risk; Systematic Reviews as Topic; Thiazolidinediones; Vitamin E

Topics: Anticholesteremic Agents; Carcinoma, Hepatocellular; Chenodeoxycholic Acid; Genetic Predisposition to Disease; Humans; Liver Neoplasms; Membrane Proteins; Non-alcoholic Fatty Liver Disease

Topics: Animals; Carcinoma, Hepatocellular; Chemokine CXCL16; Endothelial Cells; Humans; Liver Neoplasms; Mice; Mice, Inbred C57BL; Receptors, CXCR6

Despite the recent substantial progress in the treatment of hepatocellular carcinoma (HCC) from viral etiology, non-alcoholic steatohepatitis (NASH) is on a trajectory to become the fastest growing indication for HCC-related liver transplantation. The Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily with multifaceted roles in several metabolic disorders, particularly NASH. Its role as a tumor suppressor was also highlighted. Herein, we investigated the effect of obeticholic acid (OCA), as an FXR agonist, on NASH-associated HCC (NASH-HCC) animal model induced by diethylnitrosamine and high fat choline-deficient diet, exploring the potential impact on the suppressor of cytokine signaling 3 (SOCS3)/Janus kinase 2 (Jak2)/signal transducer and activator of transcription 3 (STAT3) pathway. Results indicated that OCA treatment upregulated FXR and its key mediator, small heterodimer partner (SHP), with remarkable amelioration in the dysplastic foci observed in the NASH-HCC group. This was paralleled with noticeable downregulation of alpha fetoprotein along with reduction in interferon gamma and transforming growth factor beta-1 hepatic levels besides caspase-3 and p53 upregulation. Moreover, sirtuin-1 (SIRT-1), a key regulator of FXR that controls the regenerative response of the liver, was elevated following OCA treatment. Modulation in the SOCS3/Jak2/STAT3 signaling axis was also reported. In conclusion, OCA attenuated the development and progression of NASH-dependent HCC possibly by interfering with SOCS3/Jak2/STAT3 pathway suggesting the potential use of FXR activators in NASH-related disorders, even at later stages of the disease, to impede its progression to the more deteriorating condition of HCC.

Topics: Animals; Carcinoma, Hepatocellular; Chenodeoxycholic Acid; Janus Kinase 2; Liver Neoplasms; Male; Mice; Non-alcoholic Fatty Liver Disease; Receptors, Cytoplasmic and Nuclear; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein

Farnesoid X receptor (FXR) is a receptor for bile acids and plays an important role in the regulation of bile acid metabolism in the liver. Although FXR has been shown to affect hepatocarcinogenesis through both direct and indirect mechanisms, potential roles of FXR in epithelial–mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) remain unclear. We examined the effect of several FXR ligands on EMT-related morphological changes in HCC cell lines, such as HuH-7 and Hep3B cells. FXR agonists (chenodeoxycholic acid, GW4064, and obeticholic acid)—but not an antagonist (guggulsterone)—induced actin polymerization and expression of N-cadherin and phosphorylated focal adhesion kinase, although they were less effective than transforming growth factor β (TGF-β). FXR agonist treatment enhanced TGF-β-induced EMT morphologic changes and FXR antagonist inhibited the effect of TGF-β. Thus, FXR activation enhances EMT in HCC and FXR antagonists may be EMT-suppressing drug candidates.

Topics: Bile Acids and Salts; Cadherins; Carcinoma, Hepatocellular; Cell Line, Tumor; Chenodeoxycholic Acid; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Neoplastic; Humans; Isoxazoles; Liver; Liver Neoplasms; Receptors, Cytoplasmic and Nuclear; Transforming Growth Factor beta1