Targeted disruption of carcinoembryonic antigen-related cell adhesion molecule 1 promotes diet-induced hepatic steatosis and insulin resistance.
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.
Xu
Elaine
E
Department of Anatomy, Physiology and Lipid Research Unit, Laval University Hospital Research Centre, Québec, Canada.
Dubois
Marie-Julie
MJ
Leung
Nelly
N
Charbonneau
Alexandre
A
Turbide
Claire
C
Avramoglu
Rita Kohen
RK
DeMarte
Luisa
L
Elchebly
Mounib
M
Streichert
Thomas
T
Lévy
Emile
E
Beauchemin
Nicole
N
Marette
André
A
D000818:Animals; D015153:Blotting, Western; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002784:Cholesterol / Q000097:blood; D004041:Dietary Fats / Q000494:pharmacology*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008075:Lipoproteins, HDL / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014280:Triglycerides / Q000097:blood
D015815:Cell Adhesion Molecules; D004041:Dietary Fats; D007328:Insulin; D008075:Lipoproteins, HDL; D014280:Triglycerides; D002784:Cholesterol