Mig-6 plays a critical role in the regulation of cholesterol homeostasis and bile acid synthesis.
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.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
Bon Jeong
BJ
Ku
Tae Hoon
TH
Kim
Jae Hee
JH
Lee
Eric D
ED
Buras
Lisa D
LD
White
Robert D
RD
Stevens
Olga R
OR
Ilkayeva
James R
JR
Bain
Christopher B
CB
Newgard
Francesco J
FJ
DeMayo
Jae-Wook
JW
Jeong
D000818:Animals; D001391:Azo Compounds; D001647:Bile Acids and Salts / Q000032:analysis / Q000096:biosynthesis*; D015153:Blotting, Western; D002318:Cardiovascular Diseases / Q000209:etiology*; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D005243:Feces / Q000737:chemistry; D005786:Gene Expression Regulation / Q000235:genetics*; D006706:Homeostasis / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D051379:Mice; D046228:Microarray Analysis; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001391:Azo Compounds; D001647:Bile Acids and Salts; C475819:Errfi1 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D002784:Cholesterol; C011049:oil red O