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Papers In Press, published online ahead of print May 16, 2004
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Department of Atherosclerosis, Bristol-Myers Squibb Company, Pennington, NJ 08534
Corresponding Author: ranjan.mukherjee{at}bms.com
Liver X receptors (LXRs) are ligand activated transcription factors that belong to the nuclear receptor superfamily. LXRs activate transcription of a spectrum of genes that regulate reverse cholesterol transport including the ATP binding cassette transporter A1 (ABCA1) and raise HDL cholesterol levels. However, LXR agonists also induce genes that stimulate lipogenesis including the sterol response element binding protein (SREBP1-c) and fatty acid synthetase (FAS). The induction of these genes in the liver cause increased hepatic triglyceride synthesis, hypertriglyceridemia and hepatic steatosis. Since LXR response elements have been identified in these promoters, it is not clear if these two processes can be separated. Herein, we demonstrate that plasma HDL cholesterol elevation and intestinal ABCA1 induction can occur with relatively little induction of FAS and SREBP1-c in mouse liver via a selective LXR modulator GW3965. This is in contrast to the strong induction of hepatic lipogenic genes by the well characterized LXR agonist T0901317. Consistent with the in vivo results, GW3965 is a very weak LXR activator compared to T0901317 in HepG2 cells. GW3965 liganded LXR recruits selected coactivators less effectively that T0901317 and may explain in part the tissue selective gene induction. This demonstration that tissue and gene selective modulation is possible with selective LXR modulators (SLRMs) has positive implications for the development of this class of anti-atherosclerotic agents.
Revised on May 12, 2004
Accepted on May 13, 2004
Raising HDL cholesterol without inducing hepatic steatosis and hypertriglyceridemia by a selective LXR modulator
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