on February 5, 2004
Published online before print February 5, 2004, doi: 10.1161/01.ATV.0000121202.72593.da
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Submitted on January 2, 2004
Accepted on January 27, 2004
Role of p160 Coactivator Complex in the Activation of Liver X Receptor
Jarkko Huuskonen *;
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.
* To whom correspondence should be addressed. 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 DR4 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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