Exendin‐4, a glucagon‐like protein‐1 (GLP‐1) receptor agonist, reverses hepatic steatosis in ob/ob mice†

Abstract

Nonalcoholic fatty liver disease (NAFLD) represents a burgeoning problem in hepatology, and is associated with insulin resistance. Exendin-4 is a peptide agonist of the glucagon-like peptide (GLP) receptor that promotes insulin secretion. The aim of this study was to determine whether administration of Exendin-4 would reverse hepatic steatosis in ob/ob mice. N onalcoholic fatty liver disease (NAFLD) is reported in some Western countries to be the most common liver disease, surpassing the prevalence of chronic hepatitis C virus or alcoholic liver disease. 1 NAFLD represents a disease spectrum ranging from simple steatosis to steatohepatitis and fibrosis. Approximately 3% of patients afflicted with NAFLD will develop cirrhosis. 2,3 At present, the central pathophysiological problem in patients afflicted with NAFLD is insulin resistance. Thus, there is a clear association between NAFLD and the metabolic syndrome that includes type 2 diabetes mellitus, obesity, hypertension, and hyperlipidemia. Improvement of insulin resistance, or insulin sensitivity, has therapeutic potential in preventing the progression of NAFLD because the accumulation of triglycerides in hepatocytes is believed to be the first step in the current two-hit hypothesis of the pathophysiological development of NAFLD. 4 Hence, it is hypothesized that improving insulin sensitivity would reduce hepatocyte triglyceride accumulation, thereby preventing the second step of hepatocyte vulnerability to oxidative stress. 4 Exendin-4 is a 39 amino acid agonist of the glucagonlike peptide 1 (GLP-1) receptor. Exendin-4 is present in the saliva of the Gila monster, Heloderma suspectum. 5 GLP-1, a gastrointestinal hormone secreted by the L cells of the intestine, regulates blood glucose primarily via stimulation of glucose-dependent insulin release. However, the major drawback of its clinical use is its short biological half-life, necessitating continuous administra-

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