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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:703.)
© 2004 American Heart Association, Inc.

Vascular Biology

Role of p160 Coactivator Complex in the Activation of Liver X Receptor

Jarkko Huuskonen; Phoebe E. Fielding; Christopher J. Fielding

From the Cardiovascular Research Institute (J.H., P.E.F., C.J.F.) and Departments of Medicine (P.E.F.) and Physiology (C.J.F.), University of California, San Francisco.

Correspondence to Jarkko Huuskonen, University of California San Francisco, Cardiovascular Research Institute, Box 0130, San Francisco, CA 94143-0130. E-mail jhuu6676{at}itsa.ucsf.edu

Objective— Liver X receptor (LXR) is a member of a nuclear receptor family regulating the expression of several key proteins involved in lipid metabolism and inflammation. In contrast to several other nuclear receptors, very little is known about the coactivators needed for the agonist-mediated transactivation by LXR. In this study, we have investigated the role of p160 coactivator complex in the regulation of ATP-binding transporter A1 (ABCA1), a clinically important gene transcriptionally upregulated by LXR/RXR (retinoid X receptor) heterodimer.

Methods and Results— Overexpression of LXR, SRC-1, and p300, either alone or in combination, increased the luciferase activity driven by the wild-type ABCA1 promoter. The same coactivators bound to the ABCA1 promoter on oxysterol induction in chromatin immunoprecipitation assays. To the contrary, CARM-1 and P/CAF had no effect on ABCA1 transactivation, nor do they bind the promoter. When the DR-4 element was mutated from the ABCA1 promoter, only p300 was able to activate ABCA1 transcription in a ligand-independent manner.

Conclusions— The p160 coactivator complex members SRC-1 and p300, but not CARM-1 and P/CAF, coactivate LXR-mediated transcription of ABCA1 gene. In addition, p300 activates ABCA1 transcription independently of DR-4 element and LXR/RXR.

Key Words: LXR • ABCA1 • HDL • coactivator • transcriptional regulation

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