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J. Biol. Chem., Vol. 283, Issue 2, 700-707, January 11, 2008

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Endogenous 24(S),25-Epoxycholesterol Fine-tunes Acute Control of Cellular Cholesterol Homeostasis^*

Jenny Wong¹, Carmel M. Quinn², Ingrid C. Gelissen³, and Andrew J. Brown⁴

From the School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney 2052, Australia and the Centre for Vascular Research, University of New South Wales, and the Department of Haematology, Prince of Wales Hospital, Sydney 2032, Australia

Certain oxysterols, when added to cultured cells, are potent regulators of cholesterol homeostasis, decreasing cholesterol synthesis and uptake and increasing cholesterol efflux. However, very little is known about whether or not endogenous oxysterol(s) plays a significant role in cholesterol homeostasis. 24(S),25-Epoxycholesterol (24,25EC) is unique among oxysterols in that it is produced in a shunt of the mevalonate pathway which also produces cholesterol. We investigated the role of endogenously produced 24,25EC using a novel strategy of overexpressing the enzyme 2,3-oxidosqualene cyclase in Chinese hamster ovary cells to selectively inhibit the synthesis of this oxysterol. First, loss of 24,25EC decreased expression of the LXR target gene, ABCA1, substantiating its role as an endogenous ligand for LXR. Second, loss of 24,25EC increased acute cholesterol synthesis, which was rationalized by a concomitant increase in HMG-CoA reductase gene expression at the level of SREBP-2 processing. Therefore, in the absence of 24,25EC, fine-tuning of the acute regulation of cholesterol homeostasis is lost, supporting the hypothesis that 24,25EC functions to protect the cell against the accumulation of newly synthesized cholesterol.

Received for publication, August 3, 2007 , and in revised form, October 11, 2007.

^* This work was supported in part by National Health and Medical Research Council Grant NHMRC 350828. 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 Supported by an Australian postgraduate award.

² Supported by National Health and Medical Research Council Atherosclerosis Program 222722.

³ Supported by a University of New South Wales Vice-Chancellor's postdoctoral fellowship.

⁴ To whom correspondence should be addressed: School of Biotechnology and Biomolecular Sciences, Biosciences Bldg. D26, University of New South Wales, Sydney, 2052, Australia. Tel.: 61-2-9385-2005; Fax: 61-2-9385-1483; E-mail: aj.brown{at}unsw.edu.au.

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