Exenatide induces carcinoembryonic antigen-related cell adhesion molecule 1 expression to prevent hepatic steatosis.

Exenatide, a glucagon-like peptide-1 receptor agonist, induces insulin secretion. Its role in insulin clearance has not been adequately examined. Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) promotes hepatic insulin clearance to maintain insulin sensitivity. Feeding C57BL/6J mice a high-fat diet down-regulates hepatic transcription to cause hyperinsulinemia, insulin resistance, and hepatic steatosis, as in null mice ( ). Thus, we tested whether exenatide regulates expression in high-fat diet-fed mice and whether this contributes to its insulin sensitizing effect. Exenatide (100 nM) induced the transcriptional activity of wild-type promoter but not the constructs harboring block mutations of peroxisome proliferator-activated receptor response element and retinoid X receptor alpha, individually or collectively, in HepG2 human hepatoma cells. Chromatin immunoprecipitation analysis demonstrated binding of peroxisome proliferator-activated receptor gamma to promoter in response to rosiglitazone and exenatide. Consistently, exenatide induced messenger RNA expression within 12 hours in the absence but not in the presence of the glucagon-like peptide-1 receptor antagonist exendin 9-39. Exenatide (20 ng/g body weight once daily intraperitoneal injection in the last 30 days of feeding) restored hepatic expression and insulin clearance to curb diet-induced metabolic abnormalities and steatohepatitis in wild-type but not mice fed a high-fat diet for 2 months. : Exenatide promotes insulin clearance in parallel with insulin secretion to prevent chronic hyperinsulinemia and the resulting hepatic steatosis, and this contributes to its insulin sensitizing effect. Our data further highlight the relevance of physiologic insulin metabolism in maintaining insulin sensitivity and normal lipid metabolism. ( 2018;2:35-47).