Exenatide Prevents Fat Accumulation in Liver By Inducing Hepatic CEACAM1 Expression Via a PPARγ-Dependent Mechanism

Presentation Number: OR09-5
Date of Presentation: April 4th, 2017

Hilda E Ghadieh*1, Harrison T Muturi2, Christopher C Marino1, Saja S Khuder1, Lucia Russo1, Zachary N Smiley1, Julie C Hanna1, Cara Gatto-Weis3, Garrett Heinrich2 and Sonia M Najjar2
1University of Toledo College of Medicine and Life Sciences, Toledo, OH, 2Ohio University, Athens, OH, 3University of Toledo, Toledo, OH

Abstract

Exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, induces insulin secretion from pancreatic β-cells. Its role in hepatic insulin clearance has not been adequately examined. We herein tested the hypothesis that Exenatide induces insulin clearance in liver in order to prevent chronic hyperinsulinemia and resulting hepatic fat accumulation in response to elevated insulin release. Consistent with a role of the Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) in promoting hepatic insulin clearance, feeding C57BL/6J wild-type mice a high-fat diet for 21 days reduces Ceacam1 expression to cause hyperinsulinemia followed by insulin resistance and hepatic steatosis, similar to the phenotype of Ceacam1 mutants. Thus, we fed C57BL/6J wild-type and Cc1–/– mice a high-fat diet for 2 months and subjected them to once daily intraperitoneal injection of either saline or Exenatide (20 ng/g body weight) in the last 30 days of feeding. Exenatide administration induced glucose stimulated insulin secretion and suppressed food intake in C57BL/6J wild-type and Cc1–/–. In addition, it reversed the adverse effect of high-fat diet on hepatic Ceacam1 expression and insulin clearance in parallel to curbing diet-induced metabolic abnormalities and steatohepatitis in C57BL/6J wild-type but not Cc1–/– mice, suggesting a Ceacam1-dependent mechanism. While this could result from the commonly known positive effect of insulin on Ceacam1 transcription, we tested whether Exenatide could directly regulate Ceacam1 expression in HepG2 human hepatoma cells. Exenatide (100 nM) induced the promoter activity of the wild-type, but not the Ceacam1 promoter bearing a mutant peroxisome proliferator-activated receptor response element (PPRE), consistent with its activation of PPARγ. Moreover, Exenatide induced Ceacam1 mRNA in HepG2 within 12 hours of treatment. Collectively, this demonstrates that Exenatide promotes insulin clearance pathways by inducing CEACAM1-dependent insulin clearance, and that this contributes to its insulin sensitizing effect.

 

Nothing to Disclose: HEG, HTM, CCM, SSK, LR, ZNS, JCH, CG, GH, SMN