A new mechanism of action of glucagon‐like peptide‐1 agonist in hepatic steatosis: Promotion of hepatic insulin clearance through induction of carcinoembryonic antigen‐related cell adhesion molecule 1

Nonalcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases in industrialized countries, with approximately 30%-40% of adults suffering from NAFLD. Of those, 15%-20% will develop to its progressive entity nonalcoholic steatohepatitis (NASH), a condition that may further progress to liver fibrosis and cirrhosis. Because insulin resistance and visceral obesity are major contributors in the pathogenesis of NAFLD/ NASH, weight loss, exercise, and insulin-sensitizing drugs are considered as primary treatment regimens. Obeticholic acid, a farnesoid X nuclear receptor agonist, previously approved for the treatment for primary biliary cholangitis, is currently in a phase III trial for patients with NASH fibrosis. In the United States, no effective treatments for NAFLD/NASH have been approved by the U.S. Food and Drug Administration. Potential therapeutic agents for NAFLD include antidiabetic medications, such as pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARc) agonist, and exenatide, a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist. GLP-1 is derived from the proglucagon molecule. In pancreatic a cells, the proglucagon molecule is processed to glucagon, which increases blood glucose levels. In the gut, GLP-1 and GLP-2 are produced from the same proglucagon molecule. Interestingly, GLP-1 suppresses blood glucose levels by stimulating pancreatic b cells to secrete insulin, which is in contrast to glucagon. Because the mechanism of action of GLP-1 receptor agonists is to stimulate insulin secretion to improve insulin resistance and sensitivity, exenatide has been shown to reverse steatohepatitis and is thus a potential therapeutic agent. The protease dipeptidyl peptide4 has been shown to degrade native GLP-1. Notably, exenatide degrades dipeptidyl peptide-4 to maintain the levels of endogenous GLP-1. Although GLP-1mediated insulin secretion in pancreatic b cells has been well documented, the role of GLP-1 signaling and exenatide’s mechanism of action, which is thought to include the induction of carcinoembryonic antigenAbbreviations: CEACAM1, carcinoembryonic antigen-related cell adhesion molecule 1; FASN, fatty acid synthase; GLP-1, glucagonlike peptide-1; HFD, high-fat diet; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; PPARc, peroxisome proliferator-activated receptor gamma.