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J. Biol. Chem., Vol. 283, Issue 1, 332-340, January 4, 2008

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OSBP-related Protein 8 (ORP8) Suppresses ABCA1 Expression and Cholesterol Efflux from Macrophages^*

Daoguang Yan, Mikko I. Mäyränpää^¶, Jenny Wong^||, Julia Perttilä, Markku Lehto, Matti Jauhiainen, Petri T. Kovanen, Christian Ehnholm, Andrew J. Brown^||, and Vesa M. Olkkonen¹

From the Department of Molecular Medicine, National Public Health Institute, Biomedicum, FI-00251 Helsinki, Finland, Wihuri Research Institute, FI-00140 Helsinki, Finland, ^¶Department of Forensic Medicine, University of Helsinki, FI-00014 Helsinki, Finland, and ^||School of Biotechnology and Biomolecular Sciences, The University of New South Wales, Sydney 2052, Australia

ORP8 is a previously unexplored member of the family of oxysterol-binding protein-related proteins (ORP). We now report the expression pattern, the subcellular distribution, and data on the ligand binding properties and the physiological function of ORP8. ORP8 is localized in the endoplasmic reticulum (ER) via its C-terminal transmembrane span and binds 25-hydroxycholesterol, identifying it as a new ER oxysterol-binding protein. ORP8 is expressed at highest levels in macrophages, liver, spleen, kidney, and brain. Immunohistochemical analysis revealed ORP8 in the shoulder regions of human coronary atherosclerotic lesions, where it is present in CD68(+) macrophages. In advanced lesions the ORP8 mRNA was up-regulated 2.7-fold as compared with healthy coronary artery wall. Silencing of ORP8 by RNA interference in THP-1 macrophages increased the expression of ATP binding cassette transporter A1 (ABCA1) and concomitantly cholesterol efflux to lipid-free apolipoprotein A-I but had no significant effect on ABCG1 expression or cholesterol efflux to spherical high density lipoprotein HDL₂. Experiments employing an ABCA1 promoter-luciferase reporter confirmed that ORP8 silencing enhances ABCA1 transcription. The silencing effect was partially attenuated by mutation of the DR4 element in the ABCA1 promoter and synergized with that of the liver X receptor agonist T0901317. Furthermore, inactivation of the E-box in the promoter synergized with ORP8 silencing, suggesting that the suppressive effect of ORP8 involves both the liver X receptor and the E-box functions. Our data identify ORP8 as a negative regulator of ABCA1 expression and macrophage cholesterol efflux. ORP8 may, thus, modulate the development of atherosclerosis.

Received for publication, June 28, 2007 , and in revised form, October 22, 2007.

^* This work was supported by Academy of Finland Grants 206298, 113013, and 118720 (to V. M. O.), the Sigrid Juselius Foundation (to V. M. O. and M. J.), the Finnish Foundation for Cardiovascular Research (to V. M. O. and M. J.), the Magnus Ehrnrooth Foundation (to C. E. and V. M. O.), and the Finnish Society of Sciences and Letters (to C. E. and V. M. O.). 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: Dept. of Molecular Medicine, National Public Health Institute, Biomedicum, P. Box 104, FI-00251 Helsinki, Finland. Tel.: 358-9-4744-8286; Fax: 358-9-4744-8960; E-mail: vesa.olkkonen{at}ktl.fi.

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