obeticholic-acid and Liver-Neoplasms

Farnesoid X receptor (FXR) is a ligand-activated transcription factor involved in the control of bile acid (BA) synthesis and enterohepatic circulation. FXR can influence glucose and lipid homeostasis. Hepatic FXR activation by obeticholic acid is currently used to treat primary biliary cholangitis. Late-stage clinical trials investigating the use of obeticholic acid in the treatment of nonalcoholic steatohepatitis are underway. Mouse models of metabolic disease have demonstrated that inhibition of intestinal FXR signalling reduces obesity, insulin resistance and fatty liver disease by modulation of hepatic and gut bacteria-mediated BA metabolism, and intestinal ceramide synthesis. FXR also has a role in the pathogenesis of gastrointestinal and liver cancers. Studies using tissue-specific and global Fxr-null mice have revealed that FXR acts as a suppressor of hepatocellular carcinoma, mainly through regulating BA homeostasis. Loss of whole-body FXR potentiates progression of spontaneous colorectal cancer, and obesity-induced BA imbalance promotes intestinal stem cell proliferation by suppressing intestinal FXR in Apc

Topics: Animals; Antineoplastic Agents; Bile Acids and Salts; Biomarkers; Chenodeoxycholic Acid; Gastrointestinal Agents; Gastrointestinal Microbiome; Gastrointestinal Neoplasms; Humans; Liver Neoplasms; Metabolic Diseases; Mice; Receptors, Cytoplasmic and Nuclear; Signal Transduction

Treatment with obeticholic acid (OCA) affects the blood lipid profile. Therefore, a meta-analysis of randomized controlled trials (RCTs) was performed to investigate the effects of OCA on blood lipids and lipoproteins.. The electronic databases of PubMed, Web of Science, SCOPUS, and Google Scholar were searched. The mean differences were meta-analyzed to obtain a pooled weighted mean difference (WMD) and the 95% CI across the trials using the Der Simonian and Laird random-effects method. Six (6) articles with 10 trials for low-density lipoprotein cholesterol (LDL-C), and 8 trials for high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG) levels were included in the meta-analysis. . Most studies were conducted in patients with liver dysregulation (fatty liver, liver cancer). The pooled results showed that the levels of TC (WMD: 6.357 mg/dl) and LDL-C (WMD: 6.067 mg/dl) increased while TG (WMD: -22.417 mg/dl) decreased after treatment with OCA. A slight but significant decrease was also observed for HDL-C levels (WMD: -1.492 mg/dl). A significant non-linear response was observed only between the TG levels and the length of intervention. Larger reductions in TG levels were observed over intervention durations of less than 3 weeks, but regarding interventions for more than 3 weeks, the impact on TG was modest.. OCA administration causes significant increases in blood levels of TC and LDL-C while decreasing HDL-C and TG in humans. More study needed on liver cancer.

Topics: Chenodeoxycholic Acid; Humans; Lipids; Lipoproteins; Liver Diseases; Liver Neoplasms; Randomized Controlled Trials as Topic; Treatment Outcome

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

In the last years new evidence has accumulated on nonalcoholic fatty liver disease (NAFLD) challenging the paradigms that had been holding the scene over the previous 30 years. NAFLD has such an epidemic prevalence as to make it impossible to screen general population looking for NAFLD cases. Conversely, focusing on those cohorts of individuals exposed to the highest risk of NAFLD could be a more rational approach. NAFLD, which can be diagnosed with either non-invasive strategies or through liver biopsy, is a pathogenically complex and clinically heterogeneous disease. The existence of metabolic as opposed to genetic-associated disease, notably including "lean NAFLD" has recently been recognized. Moreover, NAFLD is a systemic condition, featuring metabolic, cardiovascular and (hepatic/extra-hepatic) cancer risk. Among the clinico-laboratory features of NAFLD we discuss hyperuricemia, insulin resistance, atherosclerosis, gallstones, psoriasis and selected endocrine derangements. NAFLD is a precursor of type 2 diabetes (T2D) and metabolic syndrome and progressive liver disease develops in T2D patients in whom the course of disease is worsened by NAFLD. Finally, lifestyle changes and drug treatment options to be implemented in the individual patient are also critically discussed. In conclusion, this review emphasizes the new concepts on clinical and pathogenic heterogeneity of NAFLD, a systemic disorder with a multifactorial pathogenesis and protean clinical manifestations. It is highly prevalent in certain cohorts of individuals who are thus potentially amenable to selective screening strategies, intensive follow-up schedules for early identification of liver-related and extrahepatic complications and in whom earlier and more aggressive treatment schedules should be carried out whenever possible.

Topics: Biomarkers; Chenodeoxycholic Acid; Diabetes Mellitus, Type 2; Diagnostic Imaging; Diet, Reducing; Dyslipidemias; Exercise Therapy; Humans; Hyperuricemia; Hypoglycemic Agents; Liver; Liver Function Tests; Liver Neoplasms; Mass Screening; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; Prevalence; Risk Assessment; Risk Factors; 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