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

Department of Anatomy, Physiology and Lipid Research Unit (E.X., M.-J.D., A.C., R.K.A., A.M.), Laval University Hospital Research Centre, Québec, Canada G1V 4G2; Goodman Cancer Centre (N.L., C.T., L.D., N.B.) and Departments of Biochemistry, Medicine, and Oncology (N.L., N.B.), McGill University, Montréal, Québec, Canada H3G 1Y6; Department of Nutrition (M.E., E.L.), Research Centre of Ste. Justine Hospital and University of Montreal, Montréal, Québec, Canada H3T 1C5; and Institute of Clinical Chemistry (T.S.), University Hospital Hamburg-Eppendorf, D-20249 Hamburg, Germany

Address request for reprints: André Marette, Ph.D., Department of Anatomy-Physiology and Lipid Research Unit, Laval University Hospital Research Centre, 2705 Boulevard Laurier, RC 9600, Ste-Foy, Québec, Canada G1V 4G2. E-mail: andre.marette{at}crchul.ulaval.ca.

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- 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.

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