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

Abstract

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 Ceacam1 transcription to cause hyperinsulinemia, insulin resistance, and hepatic steatosis, as in Ceacam1 null mice (Cc1 –/–). Thus, we tested whether exenatide regulates Ceacam1 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 Ceacam1 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 Ceacam1 promoter in response to rosiglitazone and exenatide. Consistently, exenatide induced Ceacam1 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 Ceacam1 expression and insulin clearance to curb diet‐induced metabolic abnormalities and steatohepatitis in wild‐type but not Cc1 –/– mice fed a high‐fat diet for 2 months. Conclusion: 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. (Hepatology Communications 2018;2:35–47)

Loss of Hepatic Carcinoembryonic Antigen‐Related Cell Adhesion Molecule 1 Links Nonalcoholic Steatohepatitis to Atherosclerosis

“…The importance of these findings is supported by the reported lower hepatic CEACAM1 levels in patients with insulin‐resistant obesity with NAFLD ( 48 ) and the attribution of hyperinsulinemia to impaired insulin clearance in these patients. ( 49 ) With Ceacam1 expression being induced ( 50 ) by most of the drugs that are used to treat these patients, ( 4 ) the current studies provide impetus to test whether CEACAM1 is a potential target for drug development against the cardiometabolic anomalies of metabolic syndrome.…”

CEACAM1 in Liver Injury, Metabolic and Immune Regulation

“…Adenoviral-mediated reintroduction of intact wild-type CEACAM1 in hepatocytes protects against the adverse negative metabolic effects of a high-fat (HF) diet: These include hyperinsulinemia, hepatic lipid production and steatohepatitis [ 134 , 136 ]. Similarly, treatment of HF-fed wild-type mice with exenatide, a long-acting glucagon-like peptide-1 receptor agonist that stimulates insulin secretion, prevented diet-induced insulin resistance and altered metabolism by restoring hepatic CEACAM1 expression via a PPARγ-dependent pathway [ 137 ]. Exenatide treatment also protected against diet-induced steatohepatitis [ 137 , 138 ] and activation of the pro-fibrogenic TGFβ-Smad2/3 signaling pathway [ 138 ].…”

“…Similarly, treatment of HF-fed wild-type mice with exenatide, a long-acting glucagon-like peptide-1 receptor agonist that stimulates insulin secretion, prevented diet-induced insulin resistance and altered metabolism by restoring hepatic CEACAM1 expression via a PPARγ-dependent pathway [ 137 ]. Exenatide treatment also protected against diet-induced steatohepatitis [ 137 , 138 ] and activation of the pro-fibrogenic TGFβ-Smad2/3 signaling pathway [ 138 ]. Collectively, these studies emphasize the importance of the regulation of insulin sensitivity by homeostatic insulin levels, which are in turn, regulated by insulin secretion from pancreatic β cells as well as by its hepatic extraction.…”

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

“…Subsequently, the suppressive effect of FASN is removed, leading to hyperinsulinemia-driven lipogenesis. (1,5) In the present issue of Hepatology Communications, Ghadieh et al (6) provide new evidence that a GLP-1 agonist, exenatide, improves hepatic steatosis by regulating hepatic insulin clearance through induction of CEACAM1 in mice.…”

“…In the present issue of Hepatology Communications , Ghadieh et al provide new evidence that a GLP‐1 agonist, exenatide, improves hepatic steatosis by regulating hepatic insulin clearance through induction of CEACAM1 in mice.…”