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The disruption of cholesterol homeostasis leads to an increase in cholesterol levels which results in the development of cardiovascular disease. Mitogen Inducible Gene 6 ( Mig-6 ) is an immediate early response gene that can be induced by various mitogens, stresses, and hormones. To identify the metabolic role of  Mig-6  in the liver, we conditionally ablated  Mig-6  in the liver using the Albumin-Cre mouse model ( Alb cre/+ Mig-6 f/f  ;  Mig-6 d/d  ).  Mig-6 d/d   mice exhibit hepatomegaly and fatty liver. Serum levels of total, LDL, and HDL cholesterol and hepatic lipid were significantly increased in the  Mig-6 d/d   mice. The daily excretion of fecal bile acids was significantly decreased in the  Mig-6 d/d   mice. DNA microarray analysis of mRNA isolated from the livers of these mice showed alterations in genes that regulate lipid metabolism, bile acid, and cholesterol synthesis, while the expression of genes that regulate biliary excretion of bile acid and triglyceride synthesis showed no difference in the  Mig-6 d/d   mice compared to  Mig-6 f/f   controls. These results indicate that  Mig-6  plays an important role in cholesterol homeostasis and bile acid synthesis. Mice with liver specific conditional ablation of  Mig-6  develop hepatomegaly and increased intrahepatic lipid and provide a novel model system to investigate the genetic and molecular events involved in the regulation of cholesterol homeostasis and bile acid synthesis. Defining the molecular mechanisms by which  Mig-6  regulates cholesterol homeostasis will provide new insights into the development of more effective ways for the treatment and prevention of cardiovascular disease.

Mig-6 Plays a Critical Role in the Regulation of Cholesterol Homeostasis and Bile Acid Synthesis