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Cross-Talk between Peroxisome Proliferator-Activated Receptor (PPAR) and Liver X Receptor (LXR) in Nutritional Regulation of Fatty Acid Metabolism. II. LXRs Suppress Lipid Degradation Gene Promoters through Inhibition of PPAR Signaling

Department of Internal Medicine (T.I., H.S., T.M., M.N., S.Y., A.T., H.S., N.S.), Institute of Clinical Medicine, University of Tsukuba, Ibaraki 305-8575, Japan; and Department of Metabolic Diseases (T.Y., N.Y., M.A.-K., Y.I., S.T., K.O., T.G., J.O., S.I.), Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, 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, Tsukuba, Ibaraki 305-8575, Japan. E-mail: shimano-tky{at}umin.ac.jp.

Fatty acid metabolism is transcriptionally regulated by two reciprocal systems: peroxisome proliferator-activated receptor (PPAR) controls fatty acid degradation, whereas sterol regulatory element-binding protein-1c activated by liver X receptor (LXR) regulates fatty acid synthesis. To explore potential interactions between LXR and PPAR, the effect of LXR activation on PPAR signaling was investigated. In luciferase reporter gene assays, overexpression of LXR or ß suppressed PPAR-induced peroxisome proliferator response element-luciferase activity in a dose-dependent manner. LXR agonists, T0901317 and 22(R)-hydroxycholesterol, dose dependently enhanced the suppressive effects of LXRs. Gel shift assays demonstrated that LXR reduced binding of PPAR/retinoid X receptor (RXR) to peroxisome proliferator response element. Addition of increasing amounts of RXR restored these inhibitory effects in both luciferase and gel shift assays, suggesting the presence of RXR competition. In vitro protein binding assays demonstrated that activation of LXR by an LXR agonist promoted formation of LXR/RXR and, more importantly, LXR/PPAR heterodimers, leading to a reduction of PPAR/RXR formation. Supportively, in vivo administration of the LXR ligand to mice and rat primary hepatocytes substantially decreased hepatic mRNA levels of PPAR-targeted genes in both basal and PPAR agonist-induced conditions. The amount of nuclear PPAR/RXR heterodimers in the mouse livers was induced by treatment with PPAR ligand, and was suppressed by superimposed LXR ligand. Taken together with data from the accompanying paper (Yoshikawa, T., T. Ide, H. Shimano, N. Yahagi, M. Amemiya-Kudo, T. Matsuzaka, S. Yatoh, T. Kitamine, H. Okazaki, Y. Tamura, M. Sekiya, A. Takahashi, A. H. Hasty, R. Sato, H. Sone, J. Osuga, S. Ishibashi, and N. Yamada, Endocrinology 144:1240–1254) describing PPAR suppression of the LXR-sterol regulatory element-binding protein-1c pathway, we propose the presence of an intricate network of nutritional transcription factors with mutual interactions, resulting in efficient reciprocal regulation of lipid degradation and lipogenesis.

NURSA Molecule Pages Link:

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

Coregulators:   CBP  |  p300

Ligands:   22α-Hydroxycholesterol  |  T0901317  |  Pirinixic acid

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