Targeted disruption of carcinoembryonic antigen-related cell adhesion molecule 1 promotes diet-induced hepatic steatosis and insulin resistance

Endocrinology. 2009 Aug;150(8):3503-12. doi: 10.1210/en.2008-1439. Epub 2009 Apr 30.


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-gamma 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Cell Adhesion Molecules / physiology*
  • Cholesterol / blood
  • Dietary Fats / pharmacology*
  • 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*
  • Male
  • Mice
  • Mice, Mutant Strains
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Triglycerides / blood


  • Cell Adhesion Molecules
  • Dietary Fats
  • Insulin
  • Lipoproteins, HDL
  • Triglycerides
  • Cholesterol