ATF6α stimulates cholesterogenic gene expression and de novo cholesterol synthesis.

Abstract

The activating transcription factor 6α (ATF6α) is a sensor of the endoplasmic reticulum stress response that regulates the expression of genes involved in the unfolded protein response. Here we found that forced expression of a constitutively active form of ATF6α, ATF6(N), stimulated the expression of cholesterogenic genes, including 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase, HMG-CoA synthase, and squalene synthase, and de novo cholesterol synthesis in hepatoma Huh-7 cells. An ATF6α mutant lacking the DNA-binding domain ATF6(N)ΔbZip failed to show these effects. Luciferase assays indicated that ATF6(N) overexpression stimulated the promoter activities of HMG-CoA reductase, HMG-CoA synthase, and squalene synthase. Chromatin immunoprecipitation assays revealed that ATF6(N) interacted with the promoter region of the HMG-CoA synthase gene. Collectively, these results indicate that ATF6α can regulate de novo cholesterol synthesis through stimulation of cholesterogenic gene expression.

• Authors: Ryuto Maruyama, Yuki Kamoshida, Makoto Shimizu, Jun Inoue, Ryuichiro Sato
• Journal: Bioscience, biotechnology, and biochemistry (Biosci Biotechnol Biochem) Vol. 77 Issue 8 Pg. 1734-8 ( 2013) ISSN: 1347-6947 [Electronic] England
• PMID: 23924739 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATF6 protein, human
• Activating Transcription Factor 6
• RNA, Messenger
• Cholesterol
• Hydroxymethylglutaryl CoA Reductases
• Hydroxymethylglutaryl-CoA Synthase
• Farnesyl-Diphosphate Farnesyltransferase

Topics

• Activating Transcription Factor 6 (genetics, metabolism)
• Cholesterol (biosynthesis, chemistry)
• Endoplasmic Reticulum (enzymology)
• Endoplasmic Reticulum Stress
• Farnesyl-Diphosphate Farnesyltransferase (genetics)
• Gene Expression Regulation, Enzymologic
• Humans
• Hydroxymethylglutaryl CoA Reductases (genetics)
• Hydroxymethylglutaryl-CoA Synthase (genetics)
• Promoter Regions, Genetic
• RNA, Messenger