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J. Biol. Chem., Vol. 282, Issue 14, 10290-10298, April 6, 2007

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Interaction between Sterol Regulatory Element-binding Proteins and Liver Receptor Homolog-1 Reciprocally Suppresses Their Transcriptional Activities^*

Tomohiko Kanayama¹, Mitsumi Arito¹, Kanako So¹, Satoshi Hachimura, Jun Inoue, and Ryuichiro Sato²

From the Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo, Tokyo 113-8657 and Basic Research Activities for Innovative Biosciences, Tokyo 105-0001, Japan

In previous studies it was demonstrated that sterol regulatory element-binding proteins (SREBPs) are able to interact with one of the nuclear receptors, hepatocyte nuclear receptor (HNF)-4, and that this interaction regulates transcriptional activities of these proteins (Misawa, K., Horiba, T., Arimura, N., Hirano, Y., Inoue, J., Emoto, N., Shimano, H., Shimizu, M., and Sato, R. (2003) J. Biol. Chem. 278, 36176–36182; Yamamoto, T., Shimano, H., Nakagawa, Y., Ide, T., Yahagi, N., Matsuzaka, T., Nakakuki, M., Takahashi, A., Suzuki, H., Sone, H., Toyoshima, H., Sato, R., and Yamada, N. (2004) J. Biol. Chem. 279, 12027–12035). In an attempt to identify other nuclear receptor family members affecting the SREBP transcriptional activities, we found that the liver receptor homolog (LRH)-1 suppresses them. Several types of luciferase assays revealed that coexpression of these two proteins (LRH-1 and SREBP-1a, -1c, or -2) results in reciprocal inhibition of the transcriptional activity of each protein. It was confirmed that suppression in endogenous LRH-1 by small interference RNA stimulates the mRNA levels of certain SREBP target genes and that elevation in active SREBPs in the nucleus in response to cholesterol depletion suppresses the LRH-1 activity. In vitro/in vivo glutathione S-transferase pulldown experiments demonstrated that the basic helix-loop-helix-leucine zipper domain in SREBP-2 binds to the ligand-binding domain in LRH-1. Furthermore, we found that SREBP-2 interferes with the recruitment of a coactivator of LRH-1, the peroxisome proliferator-activated receptor coactivator-1, thereby leading to the inhibition of the LRH-1 transcriptional activity. These results clearly indicate that the interaction between SREBPs and LRH-1 exerts a suppressive influence on their target gene expression responsible for cholesterol and bile acid metabolism.

Received for publication, January 10, 2007

^* This work was supported by research grants from the Ministry of Education, Science, Sports, and Culture of Japan and the program for promotion of Basic Research Activities for Innovative Biosciences. 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.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Tel.: 81-5841-5136; Fax: 81-5841-8029; E-mail: aroysato{at}mail.ecc.u-tokyo.ac.jp.

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