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Cross-Talk between Peroxisome Proliferator-Activated Receptor (PPAR) and Liver X Receptor (LXR) in Nutritional Regulation of Fatty Acid Metabolism. I. PPARs Suppress Sterol Regulatory Element Binding Protein-1c Promoter through Inhibition of LXR Signaling

Department of Metabolic Diseases (T.Y., N.Y., M.A.-K., T.K., H.O., Y.T., M.S., A.H.H., J.O., S.I.), Faculty of Medicine, Department of Applied Biological Chemistry (R.S.), Graduate School of Agricultural and Life Sciences, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan; and Department of Internal Medicine (T.I., H.S., T.M., S.Y., A.T., H.S., N.Y.), Institute of Clinical Medicine, University of Tsukuba, Ibaraki 305-8575, Japan

Address all correspondence and requests for reprints to: Hitoshi Shimano, M.D., Ph.D., Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennodai, Ibaraki 305-8575, Japan. E-mail: shimano-tky{at}umin.ac.jp.

Liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) are members of nuclear receptors that form obligate heterodimers with retinoid X receptors (RXRs). These nuclear receptors play crucial roles in the regulation of fatty acid metabolism: LXRs activate expression of sterol regulatory element-binding protein 1c (SREBP-1c), a dominant lipogenic gene regulator, whereas PPAR promotes fatty acid ß-oxidation genes. In the current study, effects of PPARs on the LXR-SREBP-1c pathway were investigated. Luciferase assays in human embryonic kidney 293 cells showed that overexpression of PPAR and dose-dependently inhibited SREBP-1c promoter activity induced by LXR. Deletion and mutation studies demonstrated that the two LXR response elements (LXREs) in the SREBP-1c promoter region are responsible for this inhibitory effect of PPARs. Gel shift assays indicated that PPARs reduce binding of LXR/RXR to LXRE. PPAR-selective agonist enhanced these inhibitory effects. Supplementation with RXR attenuated these inhibitions by PPARs in luciferase and gel shift assays, implicating receptor interaction among LXR, PPAR, and RXR as a plausible mechanism. Competition of PPAR ligand with LXR ligand was observed in LXR/RXR binding to LXRE in gel shift assay, in LXR/RXR formation in nuclear extracts by coimmunoprecipitation, and in gene expression of SREBP-1c by Northern blot analysis of rat primary hepatocytes and mouse liver RNA. These data suggest that PPAR activation can suppress LXR-SREBP-1c pathway through reduction of LXR/RXR formation, proposing a novel transcription factor cross-talk between LXR and PPAR in hepatic lipid homeostasis.

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARα  |  PPARγ  |  LXRβ  |  LXRα  |  RXRα

Coregulators:   CBP  |  p300

Ligands:   22α-Hydroxycholesterol  |  T0901317  |  Pirinixic acid  |  9-cis-Retinoic acid

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