Hypoxia-inducible factor 1α activates insulin-induced gene 2 (Insig-2) transcription for degradation of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase in the liver.

Abstract

Cholesterol synthesis is a highly oxygen-consuming process. As such, oxygen deprivation (hypoxia) limits cholesterol synthesis through incompletely understood mechanisms mediated by the oxygen-sensitive transcription factor hypoxia-inducible factor 1α (HIF-1α). We show here that HIF-1α links pathways for oxygen sensing and feedback control of cholesterol synthesis in human fibroblasts by directly activating transcription of the INSIG-2 gene. Insig-2 is one of two endoplasmic reticulum membrane proteins that inhibit cholesterol synthesis by mediating sterol-induced ubiquitination and subsequent endoplasmic reticulum-associated degradation of the rate-limiting enzyme in the pathway, HMG-CoA reductase (HMGCR). Consistent with the results in cultured cells, hepatic levels of Insig-2 mRNA were enhanced in mouse models of hypoxia. Moreover, pharmacologic stabilization of HIF-1α in the liver stimulated HMGCR degradation via a reaction that requires the protein's prior ubiquitination and the presence of the Insig-2 protein. In summary, our results show that HIF-1α activates INSIG-2 transcription, leading to accumulation of Insig-2 protein, which binds to HMGCR and triggers its accelerated ubiquitination and degradation. These results indicate that HIF-mediated induction of Insig-2 and degradation of HMGCR are physiologically relevant events that guard against wasteful oxygen consumption and inappropriate cell growth during hypoxia.

• Authors: Seonghwan Hwang, Andrew D Nguyen, Youngah Jo, Luke J Engelking, James Brugarolas, Russell A DeBose-Boyd
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 292 Issue 22 Pg. 9382-9393 (06 02 2017) ISSN: 1083-351X [Electronic] United States
• PMID: 28416613 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• HIF1A protein, human
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• INSIG2 protein, human
• Insig2 protein, mouse
• Intracellular Signaling Peptides and Proteins
• Membrane Proteins
• HMGCR protein, human
• Hydroxymethylglutaryl CoA Reductases

Topics

• Animals
• Cell Hypoxia
• Cell Line, Transformed
• Fibroblasts (metabolism)
• Humans
• Hydroxymethylglutaryl CoA Reductases (genetics, metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• Intracellular Signaling Peptides and Proteins (biosynthesis, genetics)
• Liver (metabolism)
• Membrane Proteins (biosynthesis, genetics)
• Mice
• Proteolysis
• Transcription, Genetic