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Originally published In Press as doi:10.1074/jbc.M605023200 on November 14, 2006

J. Biol. Chem., Vol. 282, Issue 1, 743-751, January 5, 2007
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The Liver X Receptor (LXR) and Hepatic Lipogenesis

THE CARBOHYDRATE-RESPONSE ELEMENT-BINDING PROTEIN IS A TARGET GENE OF LXR*Formula

Ji-Young Cha{ddagger} and Joyce J. Repa{ddagger}§1

From the Departments of {ddagger}Physiology and §Internal Medicine, Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390

The liver X receptors, LXR{alpha} (NR1H3) and LXRbeta (NR1H2), are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. LXRs play a critical role in cholesterol homeostasis and bile acid metabolism. In addition, oral administration of LXR agonists to mice results in elevated hepatic fatty acid synthesis and steatosis and increased secretion of triglyceride-rich very low density lipoprotein resulting in hypertriglyceridemia. This increased hepatic lipogenesis has been largely attributed to the LXR-dependent up-regulation of sterol regulatory element-binding protein 1c (SREBP-1c) expression. However, it has been reported that treating Srebp-1c null mice with the synthetic LXR agonist T0901317 still results in enhanced expression of many lipogenic genes, suggesting additional mechanisms by which LXR can enhance hepatic lipogenesis. In this report, we identify the carbohydrate response element-binding protein (ChREBP) as an LXR target that independently enhances the up-regulation of select lipogenic genes. The ChREBP promoter contains functional LXR-binding sites that confer receptor-dependent binding and transactivation. We show that T0901317 treatment of mice is associated with up-regulation of the ChREBP target gene, liver-type pyruvate kinase. Therefore, activation of LXR not only increases ChREBP mRNA via enhanced transcription but also modulates ChREBP activity. This establishes LXR as a master lipogenic transcription factor, as it directly regulates both SREBP-1c and ChREBP to enhance hepatic fatty acid synthesis.

Received for publication, May 25, 2006 , and in revised form, November 13, 2006.

* This work was supported by Beginning Grant-in-aid 0465115Y from the American Heart Association, Texas Affiliate, and Research Award 7-04-RA-94 from the American Diabetes Association (to J. J. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Formula The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S2 and Table S1.

1 To whom correspondence should be addressed: 5323 Harry Hines Blvd., Y6.322C, Dallas, TX 75390-9077. Tel.: 214-648-9431; Fax: 214-648-5612; E-mail: joyce.repa{at}utsouthwestern.edu.


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