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J. Biol. Chem., Vol. 282, Issue 8, 5207-5216, February 23, 2007

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Selective Up-regulation of LXR-regulated Genes ABCA1, ABCG1, and APOE in Macrophages through Increased Endogenous Synthesis of 24(S),25-Epoxycholesterol^*

Michael M. Beyea¹, Claire L. Heslop, Cynthia G. Sawyez^¶, Jane Y. Edwards^¶, Janet G. Markle, Robert A. Hegele^¶23, and Murray W. Huff^¶34

From the Robarts Research Institute Vascular Biology Group, the Department of Biochemistry, and the ^¶Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario N6A 5K8, Canada

Liver X receptor (LXR) activation represents a mechanism to prevent macrophage foam cell formation. Previously, we demonstrated that partial inhibition of oxidosqualene:lanosterol cyclase (OSC) stimulated synthesis of the LXR agonist 24(S),25-epoxycholesterol (24(S),25-epoxy) and enhanced ABCA1-mediated cholesterol efflux. In contrast to a synthetic, nonsteroidal LXR activator, TO-901317, triglyceride accumulation was not observed. In the present study, we determined whether endogenous 24(S),25-epoxy synthesis selectively enhanced expression of macrophage LXR-regulated cholesterol efflux genes but not genes that regulate fatty acid metabolism. THP-1 human macrophages incubated with the OSC inhibitor (OSCi) RO0714565 (15 nM) significantly reduced cholesterol synthesis and maximized synthesis of 24(S),25-epoxy. Endogenous 24(S),25-epoxy increased ABCA1, ABCG1, and APOE mRNA abundance and consequently increased cholesterol efflux to apoAI. In contrast, OSCi had no effect on LXR-regulated genes LPL (lipoprotein lipase) and FAS (fatty acid synthase). TO-901317 (10 nM) significantly enhanced expression of all genes examined. OSCi and TO-901317 increased the mRNA and precursor form of SREBP-1c, a major regulator of fatty acid and triglyceride synthesis. However, conversion of the precursor to the active form (nSREBP-1c) was blocked by OSCi-induced 24(S),25-epoxy but not by TO-901317 (10 nM), which instead markedly increased nSREBP-1c. Disruption of nSREBP-1c formation by 24(S),25-epoxy accounted for diminished FAS and LPL expression. In summary, endogenous synthesis of 24(S),25-epoxy selectively up-regulates expression of macrophage LXR-regulated cholesterol efflux genes without stimulating genes linked to fatty acid and triglyceride synthesis.

Received for publication, December 1, 2006

^* This work was supported by Canadian Institutes of Health Research Grant MT-8014 and Heart and Stroke Foundation of Ontario (HSFO) Grant PG-4854. 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 Recipient of a National Science and Engineering Research Council of Canada Postgraduate Scholarship and holder of a Heart and Stroke Foundation of Canada Doctoral Research Award.

² Holder of a Canada Research Chair (Tier I) in Human Genetics.

³ Career Investigator of the HSFO.

⁴ To whom correspondence should be addressed: Rm. 4-16, 100 Perth Dr., London, Ontario N6A 5K8, Canada. Tel.: 519-663-3793; Fax: 519-663-3112; E-mail: mhuff{at}uwo.ca.

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