Role of LXRs in control of lipogenesis
Abstract
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.
Liver X receptors (LXRs), LXRα (NR1H3), and LXR-β (NR1H2), are nuclear receptors that regulate the metabolism of several important lipids, including cholesterol and bile acids. LXRs were first identified as orphan members of the nuclear receptor superfamily (Song et al. 1994; Willy et al. 1995). The identification of a specific class of oxidized derivatives of cholesterol as ligands for the LXRs, in combination with the description of an LXR response element in the promoter of the rat cholesterol 7α-hydroxylase gene (CYP7A1), suggested that LXRs play an important role in the regulation of cholesterol homeostasis (Janowski et al. 1996, 1999; Lehmann et al. 1997). Additional support for this role came from the analysis of LXRα-deficient mice (LXRα−/−), which uncovered the dysregulation of the CYP7A1 gene and several other important lipid-associated genes (Peet et al. 1998). Studies utilizing these animals confirmed the essential function of LXRα as a major sensor of dietary cholesterol and an activator of the bile acid synthetic pathway in mice.
Three sterol regulatory element–binding proteins (SREBP-1a, -1c, and -2) stimulate transcription of a number of genes involved in the synthesis and receptor-mediated uptake of cholesterol and fatty acids (Brown and Goldstein 1997; Horton and Shimomura 1998). Results to date support the notion that SREBP-1 primarily activates the fatty acid, triglyceride, and phospholipid pathways, while SREBP-2 is the prominent isoform supporting cholesterol synthesis and uptake (Shimano et al. 1996; Brown and Goldstein 1997; Horton and Simomura 1998; Horton et al. 1998). In fatty acid biosynthesis, proteases release nuclear SREBP-1c (the major SREBP-1 isoform in the liver of animals), which activates transcription of the major genes of fatty acid synthesis including acetyl CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl CoA desaturase-1 (SCD-1), glycerol-3-phosphate acyltransferase, and others (Bennett et al. 1995; Lopez et al. 1996; Ericsson et al. 1997; Shimomura et al. 1998).
In this study, we describe the identification and biochemical features of a nonsteroidal LXR agonist, T0314407, and its analog T0901317. Our understanding of the in vivo role of LXR in lipid metabolism was extended by induction of LXR-regulated pathways in mice and hamsters. We show that LXR agonist treatment induces the expression of genes associated with fatty acid biosynthesis, and it raises plasma triglyceride levels in these animal models. Administration of T0901317 to mice lacking both the LXR α and β genes (LXRα/β−/−) corroborated both the requirement of LXRs in the activation of lipogenesis and their being key components of the triglyceride response. We present data that are consistent with the hypertriglyceridemic effect being associated with LXR agonist-dependent induction of the SREBP-1 lipogenic program.
Acknowledgments
We thank Matthew Wright for pharmacological evaluations of LXR agonists; Gene Cutler for bioinformatics associated with GEM data mining; Miki Rich for DNA sequencing; Heather DiMaio and Susan Shetterly for excellent technical assistance; Ronald Krauss and Patricia Blanche and the Donner Lipoprotein Analysis Core Laboratory, E.O. Lawrence National Laboratory, and University of California, Berkeley, for expert lipid analysis; and Jurgen Lehmann, Tim Hoey, Margrit Schwarz, Terry Rosen, David W. Russell, Steven L. McKnight, Michael S. Brown, and Joseph L. Goldstein, for critical reviews. D.J.M. is funded by the Howard Hughes Medical Institute, the Robert A. Welch Foundation, and the Human Frontier Science Program.
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Footnotes
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Article and publication are at www.genesdev.org/cgi/doi/10.1101/gad.850400.