HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 37, 27436-27446, September 14, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/37/27436    most recent M704976200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nguyen, A. D. Articles by DeBose-Boyd, R. A. Search for Related Content PubMed PubMed Citation Articles by Nguyen, A. D. Articles by DeBose-Boyd, R. A. Social Bookmarking                      What's this?

Hypoxia Stimulates Degradation of 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase through Accumulation of Lanosterol and Hypoxia-Inducible Factor-mediated Induction of Insigs^*

Andrew D. Nguyen¹, Jeffrey G. McDonald², Richard K. Bruick³, and Russell A. DeBose-Boyd⁴

From the Departments of Molecular Genetics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046

Endoplasmic reticulum-associated degradation of the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase represents one mechanism by which cholesterol synthesis is controlled in mammalian cells. The key reaction in this degradation is binding of reductase to Insig proteins in the endoplasmic reticulum, which is stimulated by the cholesterol precursor lanosterol. Conversion of lanosterol to cholesterol requires removal of three methyl groups, which consumes nine molecules of dioxygen. Here, we report that oxygen deprivation (hypoxia) slows demethylation of lanosterol and its metabolite 24,25-dihydrolanosterol, causing both sterols to accumulate in cells. In addition, hypoxia increases the amount of Insig-1 and Insig-2 in a response mediated by hypoxia-inducible factor (HIF)-1. Accumulation of lanosterol together with increased Insigs accelerates degradation of reductase, which ultimately slows a rate-determining step in cholesterol synthesis. These results define a novel oxygen-sensing mechanism mediated by the combined actions of methylated intermediates in cholesterol synthesis and the hypoxia-activated transcription factor HIF-1.

Received for publication, June 15, 2007 , and in revised form, July 10, 2007.

^* This work was supported by National Institutes of Health Grant HL20948 and a grant from the Perot Family Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Supported by Division of Cell and Molecular Biology Training Program Grant T32GM008203.

² Supported by National Institutes of Health LIPID MAPS Large Scale Collaborative Grant GM069338.

³ A Michael L. Rosenberg Scholar in Medical Research, supported by a grant from the Burroughs Wellcome Fund and by National Institutes of Health Grant CA115962.

⁴ Recipient of National Institutes of Health Mentored Minority Faculty Development Award HL70441, American Heart Association Established Investigator Award 0540128N, and a Distinguished Young Investigator in Medical Research Award from the W. M. Keck Foundation. To whom correspondence should be addressed. E-mail: Russell.DeBose-Boyd{at}utsouthwestern.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Y. Lange, D. S. Ory, J. Ye, M. H. Lanier, F.-F. Hsu, and T. L. Steck Effectors of Rapid Homeostatic Responses of Endoplasmic Reticulum Cholesterol and 3-Hydroxy-3-methylglutaryl-CoA Reductase J. Biol. Chem., January 18, 2008; 283(3): 1445 - 1455. [Abstract] [Full Text] [PDF]

				J. Wong, C. M. Quinn, I. C. Gelissen, and A. J. Brown Endogenous 24(S),25-Epoxycholesterol Fine-tunes Acute Control of Cellular Cholesterol Homeostasis J. Biol. Chem., January 11, 2008; 283(2): 700 - 707. [Abstract] [Full Text] [PDF]