Exenatide ameliorates hepatic steatosis and attenuates fat mass and FTO gene expression through PI3K signaling pathway in nonalcoholic fatty liver disease

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a common disease associated with metabolic syndrome and can lead to life-threatening complications like hepatic carcinoma and cirrhosis. Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist antidiabetic drug, has the capacity to overcome insulin resistance and attenuate hepatic steatosis but the specific underlying mechanism is unclear. This study was designed to investigate the underlying molecular mechanisms of exenatide therapy on NAFLD. We used in vivo and in vitro techniques to investigate the protective effects of exenatide on fatty liver via fat mass and obesity associated gene (FTO) in a high-fat (HF) diet-induced NAFLD animal model and related cell culture model. Exenatide significantly decreased body weight, serum glucose, insulin, insulin resistance, serum free fatty acid, triglyceride, total cholesterol, low-density lipoprotein, aspartate aminotransferase, and alanine aminotransferase levels in HF-induced obese rabbits. Histological analysis showed that exenatide significantly reversed HF-induced lipid accumulation and inflammatory changes accompanied by decreased FTO mRNA and protein expression, which were abrogated by PI3K inhibitor LY294002. This study indicated that pharmacological interventions with GLP-1 may represent a promising therapeutic strategy for NAFLD.

Effect of semaglutide on liver enzymes and markers of inflammation in subjects with type 2 diabetes and/or obesity

“…This is consistent with the association of excess adiposity to the pathogenesis of NAFLD, and with previous data showing a significant ALT reduction in patients with type 2 diabetes given 26 weeks of liraglutide 1.8 mg/day that was similarly attenuated after adjustment for weight change . However, weight loss is not the only mechanism by which the glucagon‐like peptide‐1 receptor agonists may exert pleiotropic beneficial effects on metabolism, steatosis, cardiovascular risk and inflammation . Thus, while these results indicate an association between weight loss and ALT change, neither causality nor sole agency can be established, and further research will be needed to evaluate other potential contributors or whether weight loss achieved by other means yields the same ALT reductions seen here.…”

RNA N6-methyladenosine: a promising molecular target in metabolic diseases

“…These indicate that FTO can affect mitochondrial content and fat metabolism by modulating m 6 A levels in hepatocytes [101]. In addition, the activation of phosphatidylinositol 3-kinase (PI3K)/ AKT signaling pathway may improve the development of NAFLD by suppressing FTO mediated hepatocyte regeneration [102]. Enhanced FTO expression can increase expression of lipogenic genes, containing fatty acid synthase (FASN), stearoyl-CoA desaturase (SCD) and monoacylglycerol O-acyltransferase 1 (MOGAT1), and intracellular TG level in HepG2 cells [101], which finally promotes hepatic fat accumulation.…”

Exenatide improves cardiovascular risk factors in obese patients with type 2 diabetes mellitus: a prospective study

“…Liver biopsy is still the gold standard for evaluating NAFLD and NASH, but has disadvantages including cost, sampling error, inter-observer variabilities and procedure related complications [28]. The sensitivity of US on NAFLD is low but the specificity of US in predicting NAFLD was found to be 94% in a meta-analysis [29]. A limitation of our study is lacking liver biopsy, but obtaining liver biopsy is beyond the aim of this study.…”