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J. Biol. Chem., Vol. 283, Issue 3, 1445-1455, January 18, 2008

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Effectors of Rapid Homeostatic Responses of Endoplasmic Reticulum Cholesterol and 3-Hydroxy-3-methylglutaryl-CoA Reductase^*

Yvonne Lange¹, Daniel S. Ory, Jin Ye, Michael H. Lanier, Fong-Fu Hsu, and Theodore L. Steck^¶

From the Department of Pathology, Rush University Medical Center, Chicago, Illinois 60612, the Department of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110, and the ^¶Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637

The cholesterol content of the endoplasmic reticulum (ER) and the activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) imbedded therein respond homeostatically within minutes to changes in the level of plasma membrane cholesterol. We have now examined the roles of sterol regulatory element-binding protein (SREBP)-dependent gene expression, side chain oxysterol biosynthesis, and cholesterol precursors in the short term regulation of ER cholesterol levels and HMGR activity. We found that SREBP-dependent gene expression is not required for the response to changes in cell cholesterol of either the pool of ER cholesterol or the rate of cholesterol esterification. It was also found that the acute proteolytic inactivation of HMGR triggered by cholesterol loading required the conversion of cholesterol to 27-hydroxycholesterol. High levels of exogenous 24,25-dihydrolanosterol drove the inactivation of HMGR; lanosterol did not. However, purging endogenous 24,25-dihydrolanosterol, lanosterol, and other biosynthetic sterol intermediates by treating cells with NB-598 did not greatly affect either the setting of their ER cholesterol pool or the inactivation of their HMGR. In summary, neither SREBP-regulated genes nor 27-hydroxycholesterol is involved in setting the ER cholesterol pool. On the other hand, 27-hydroxycholesterol, rather than cholesterol itself or biosynthetic precursors of cholesterol, stimulates the rapid inactivation of HMGR in response to high levels of cholesterol.

Received for publication, August 20, 2007 , and in revised form, November 9, 2007.

^* This work was supported by National Institutes of Health Grants HL 28448 (to Y. L.), HL67773 (to D. S. O.), and P41-RR-00954. 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.

¹ To whom correspondence should be addressed: Rush University Medical Center, 1653 W. Congress Parkway, Chicago, IL 60612. Fax: 312-563-3115; E-mail: ylange{at}rush.edu.

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