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.