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. 2012;7(8):e42915.
doi: 10.1371/journal.pone.0042915. Epub 2012 Aug 17.

Mig-6 plays a critical role in the regulation of cholesterol homeostasis and bile acid synthesis

Bon Jeong Ku  1 , Tae Hoon Kim, Jae Hee Lee, Eric D Buras, Lisa D White, Robert D Stevens, Olga R Ilkayeva, James R Bain, Christopher B Newgard, Francesco J DeMayo, Jae-Wook Jeong
Affiliations

Mig-6 plays a critical role in the regulation of cholesterol homeostasis and bile acid synthesis

Bon Jeong Ku et al. PLoS One. 2012.

Abstract

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Generation of conditional ablation of Mig-6 in the liver.
A. RT-PCR analysis of Mig-6 mRNA expression level. 8 week old Mig-6f/f and Mig-6d/d male mice were sacrificed after 24 hrs of fasting and RNA was isolated from the liver, kidney, adrenal gland, lungs, muscle, and white adipose tissue. Five mice of each group were used for this experiment. The results represent the mean ± SEM of three independent RNA sets. ***, p<0.001. B, Western blot analysis of MIG-6 in the liver of Mig-6f/f and Mig-6d/d mice. Liver tissue from Mig-6f/f and Mig-6d/d mice were lysed and equal amounts of protein were subjected to SDS-PAGE and Western blot analysis for MIG-6.
Figure 2
Figure 2. Morphology of the liver of Mig-6f/f and Mig-6d/d
mice. A, Size of liver. Twelve mice of each group were used for this experiment. B, Weight of the liver adjusted to body weight. The results represent the mean ± SEM. The numbers in parentheses are the number of mice used. ***, p<0.001. C. Oil-Red-O staining. Liver tissue were fixed with 4% paraformaldehyde (vol/vol) and frozen in OCT. Sections were counterstained with hematoxylin and mounted with 15% glycerol. All of the photomicrographs are X400 magnification.
Figure 3
Figure 3. Real-time RT-PCR analysis of metabolic genes in the liver.
A, Bile acid metabolism related genes. B, Cholesterol synthesis related genes. C, Triglyceride metabolism related genes. 8 week old Mig-6d/d and Mig-6f/f male mice were sacrificed after 24 hrs fasting and RNA was isolated from the liver. 5 mice of each group were used for this experiment. The results represent the mean ± SEM of three independent RNA sets. *, p<0.05; ***, p<0.001.
Figure 4
Figure 4. Regulation of CYP7A1 and HMGCS1 protein level in the liver of Mig-6d/d mice.
Western blot analysis for CYP7A1 and HMGCS1 in the liver of Mig-6f/f and Mig-6d/d mice. Liver tissue from Mig-6f/f and Mig-6d/d mice were lysed, and equal amounts of protein were subjected to SDS-PAGE and Western blot analysis with anti-CYP7A1 and anti-HMGCS1 antibodies.
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