Abstract
The Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 (CEACAM1) promotes insulin sensitivity by inducing insulin clearance and reducing de novo lipogenesis in the liver. Consistently, Cc1-/- mice with null deletion of Ceacam1 gene exhibit hyperinsulinemia and insulin resistance, in addition to steatohepatitis. They also exhibit early pericellular fibrosis. Redelivering Ceacam1 to the liver reverses the altered metabolism and histopathology of Cc1-/- mice. Exenatide, a long-acting glucagon-like peptide-1 receptor agonist, induces Ceacam1 transcription and consequently, reverses impaired insulin clearance and insulin resistance caused by high-fat intake. Additionally, it reverses fat accumulation in the liver. The current studies show that exenatide also restored the activities of alanine transaminase and aspartate aminotransferase, and reversed the inflammatory and oxidative stress response to high-fat diet in wild-type, but not in Cc1-/- mice. Exenatide also prevented diet-induced activation of the TGFβ/Smad2/Smad3 pro-fibrogenic pathways, and normalized the mRNA levels of pro-fibrogenic genes in wild-type, but not in Cc1-/- mice. Together, the data demonstrate that exenatide prevented diet-induced pro-fibrogenesis and hepatocellular injury in a CEACAM1-dependent mechanism.