Targeted Disruption of Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Promotes Diet-Induced Hepatic Steatosis and Insulin Resistance

• Published in: Endocrinology (Philadelphia) Vol. 150; no. 8; pp. 3503 - 3512
• Main Authors: Xu, Elaine, Dubois, Marie-Julie, Leung, Nelly, Charbonneau, Alexandre, Turbide, Claire, Avramoglu, Rita Kohen, DeMarte, Luisa, Elchebly, Mounib, Streichert, Thomas, Lévy, Emile, Beauchemin, Nicole, Marette, André
• Format: Journal Article
• Language: English
• Published: Chevy Chase, MD Endocrine Society 01.08.2009
• Subjects: Animals; Biological and medical sciences; Blotting, Western; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell Adhesion Molecules - physiology; Cholesterol - blood; Dietary Fats - pharmacology; Fundamental and applied biological sciences. Psychology; Gastroenterology. Liver. Pancreas. Abdomen; Glucose Clamp Technique; Glucose Tolerance Test; Immunoprecipitation; Insulin - metabolism; Insulin Resistance - genetics; Insulin Resistance - physiology; Lipid Metabolism - drug effects; Lipid Metabolism - genetics; Lipoproteins, HDL - blood; Liver - drug effects; Liver - metabolism; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Mice; Mice, Mutant Strains; Other diseases. Semiology; Signal Transduction - drug effects; Signal Transduction - genetics; Triglycerides - blood; Vertebrates: endocrinology; Endocrinopathy; Target tissue resistance; Carcinoembryonic antigen; Fatty liver; Diet; Cell adhesion molecule; Metabolic diseases; Digestive diseases; Hepatic disease; Insulin resistance; Disruption; Feeding
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2008-1439

Carcinoembryonic antigen-related cell adhesion molecule 1 (CC1) is a cell adhesion molecule within the Ig superfamily. The Tyr-phosphorylated isoform of CC1 (CC1-L) plays an important metabolic role in the regulation of hepatic insulin clearance. In this report, we show that CC1-deficient (Cc1−/−) mice are prone to hepatic steatosis, as revealed by significantly elevated hepatic triglyceride and both total and esterified cholesterol levels compared with age-matched wild-type controls. Cc1−/− mice were also predisposed to lipid-induced hepatic steatosis and dysfunction as indicated by their greater susceptibility to store lipids and express elevated levels of enzymatic markers of liver damage after chronic feeding of a high-fat diet. Hepatic steatosis in the Cc1−/− mice was linked to a significant increase in the expression of key lipogenic (fatty acid synthase, acetyl CoA carboxylase) and cholesterol synthetic (3-hydroxy-3-methylglutaryl-coenzyme A reductase) enzymes under the control of sterol regulatory element binding proteins-1c and -2 transcription factors. Cc1−/− mice also exhibited impaired insulin clearance, glucose intolerance, liver insulin resistance, and elevated hepatic expression of the key gluconeogenic transcriptional activators peroxisome proliferator-activated receptor-γ coactivator-1 and Forkhead box O1. Lack of CC1 also exacerbated both glucose intolerance and hepatic insulin resistance induced by high-fat feeding, but insulin clearance was not further deteriorated in the high-fat-fed Cc1−/− mice. In conclusion, our data indicate that CC1 is a key regulator of hepatic lipogenesis and that Cc1−/− mice are predisposed to liver steatosis, leading to hepatic insulin resistance and liver damage, particularly when chronically exposed to dietary fat. CEACAM1 is a key regulator of hepatic lipogenesis, and its targeted disruption in mice predisposes to liver steatosis and insulin resistance, particularly when chronically exposed to dietary fat.