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Journal of Lipid Research, Vol. 45, 1410-1417, August 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology
* Cardiovascular Biology, Bristol-Myers Squibb Company, Experimental Station, Wilmington, DE 19880
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Company, 311 Pennington Rocky Hill Road, Pennington, NJ 08534
Department of Atherosclerosis, Bristol-Myers Squibb Company, 311 Pennington Rocky Hill Road, Pennington, NJ 08534
3 To whom correspondence should be addressed. e-mail: 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 (HDL-C) 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. As 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-C 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 (T317). Consistent with the in vivo results, GW3965 is a very weak LXR activator compared with T317 in human hepatoma cells. GW3965-liganded LXR recruits selected coactivators less effectively than T317 and may explain in part the tissue selective gene induction.
This demonstration that tissue and gene selective modulation is possible with selective LXR modulators has positive implications for the development of this class of antiatherosclerotic agents.
Abbreviations: ABCA1, ATP binding cassette transporter A1; apoE, apolipoprotein E; CBP, cAMP response element binding protein; CETP, cholesteryl ester transfer protein; DRIP, vitamin D receptor-interacting proteins; FAS, fatty acid synthetase; FRET, fluorescence resonance energy transfer; GST, glutathione-S-transferase; HDL-C, HDL cholesterol; hLXR
, human LXR; LDLR, LDL receptor; LXR, liver X receptor; SLRM, selective LXR modulator; SR-BI, scavenger receptor class B type I; SRC-1, steroid receptor coactivator-1; SREBP1-c, sterol response element binding protein 1-c; T317, T0901317; TAMRA, 6-carboxytetramethylrhodamine; TG, triglyceride
Supplementary key words high density lipoprotein • liver X receptor • fatty acid synthetase • sterol response element binding protein 1-c • triglyceride
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