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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases associated with obesity, insulin resistance, and type 2 diabetes mellitus [1]
Previous studies have confirmed that hepatic steatosis mostly results from an increased free fatty acid (FFA) supply to the hepatocytes due to increased lipolysis and/or increased intake of dietary fat, which contributes to 60% of hepatic fat content [3]
The prevailing theory for the pathogenesis of NAFLD is closely associated with lipid accumulation within hepatocytes and lipotoxicity caused by oxidative stress from increased lipid peroxidation, mitochondrial dysfunction, and high ROS production
Summary
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases associated with obesity, insulin resistance, and type 2 diabetes mellitus [1]. It encompasses a variety of histological conditions ranging from simple steatosis to non-alcoholic steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma, of which cirrhosis and hepatocellular carcinoma are the two life threatening complications of NAFLD [2]. Clinical studies have shown that weight loss can improve fatty liver, and that reduced liver fat content confers lower serum fasting insulin and triglyceride (TG) concentrations relative to subjects with high levels of liver fat [4]. Weight reduction and adequate control of diabetes (main complication) is the standard treatment for NAFLD
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