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J. Biol. Chem., Vol. 282, Issue 16, 11687-11695, April 20, 2007

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Protein Kinase A Suppresses Sterol Regulatory Element-binding Protein-1C Expression via Phosphorylation of Liver X Receptor in the Liver^*

Takashi Yamamoto, Hitoshi Shimano¹, Noriyuki Inoue, Yoshimi Nakagawa, Takashi Matsuzaka, Akimitsu Takahashi, Naoya Yahagi, Hirohito Sone, Hiroaki Suzuki, Hideo Toyoshima, and Nobuhiro Yamada

From the Department of Internal Medicine, Metabolism and Endocrinology, Graduate School of Comprehensive Human Sciences and Center for Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan

Sterol regulatory element-binding protein (SREBP)-1c is a transcription factor that controls synthesis of fatty acids and triglycerides in the liver and is highly regulated by nutrition and hormones. In the current studies we show that protein kinase A (PKA), a mediator of glucagon/cAMP, a fasting signaling, suppresses SREBP-1c by modulating the activity of liver X receptor (LXR), a dominant activator of SREBP-1c expression. Activation of PKA repressed LXR-induced SREBP-1c expression both in rat primary hepatocytes and mouse livers. Promoter analyses revealed that the LXR-binding site in the SREBP-1c promoter is responsible for PKA inhibitory effect on SREBP-1c transcription. In vitro and in vivo PKA directly phosphorylated LXR, and the two consensus PKA target sites (195, 196 serines and 290, 291 serines) in its ligand binding/heterodimerization domain were crucial for the inhibition of LXR signaling. PKA phosphorylation of LXR caused impaired DNA binding activity by preventing LXR/RXR dimerization and decreased its transcription activity by inhibiting recruitment of coactivator SCR-1 and enhancing recruitment of corepressor NcoR1. These results indicate that LXR is regulated not only by oxysterol derivatives but also by PKA-mediated phosphorylation, which suggests that nutritional regulation of SREBP-1c and lipogenesis could be regulated at least partially through modulation of LXR.

Received for publication, December 29, 2006

^* This work was supported by grants-in-aid from the Ministry of Science, Education, Culture, and Technology of Japan. 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 To whom correspondence and requests should be addressed. Fax: 81-29-853-317; E-mail: shimano-tky{at}umin.ac.jp.

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