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Vol. 14, No. 22, pp. 2831-2838, November 15, 2000
1 Tularik Inc., South
San Francisco, California 94080, USA; 2 Howard Hughes
Medical Institute and Department of Pharmacology, University of
Texas Southwestern Medical Center, Dallas, Texas 75390, USA
The discovery of oxysterols as the endogenous liver X receptor (LXR)
ligands and subsequent gene targeting studies in mice provided strong
evidence that LXR plays a central role in cholesterol metabolism. The
identification here of a synthetic, nonsteroidal LXR-selective agonist
series represented by T0314407 and T0901317 revealed a novel
physiological role of LXR. Oral administration of T0901317 to mice and
hamsters showed that LXR activated the coordinate expression of major
fatty acid biosynthetic genes (lipogenesis) and increased plasma
triglyceride and phospholipid levels in both species. Complementary
studies in cell culture and animals suggested that the increase in
plasma lipids occurs via LXR-mediated induction of the sterol
regulatory element-binding protein 1 (SREBP-1) lipogenic program.
[Key Words: LXR; lipogenesis; SREBP; fatty acid; triglyceride]
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