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Journal of Lipid Research, Vol. 48, 1581-1591, July 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

SREBP-1-independent regulation of lipogenic gene expression in adipocytes

Motohiro Sekiya^*, Naoya Yahagi^*,, Takashi Matsuzaka, Yoshinori Takeuchi, Yoshimi Nakagawa, Haruka Takahashi^*, Hiroaki Okazaki^*, Yoko Iizuka^*, Ken Ohashi^*, Takanari Gotoda^*, Shun Ishibashi^*, Ryozo Nagai^*,, Tsutomu Yamazaki^*,, Takashi Kadowaki^*, Nobuhiro Yamada, Jun-ichi Osuga^* and Hitoshi Shimano^1,

^* Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
Department of Clinical Bioinformatics, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan
Advanced Biomedical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki 305-8575, Japan

Published, JLR Papers in Press, April 24, 2007.

¹ To whom correspondence should be addressed. e-mail: shimano-tky{at}umin.ac.jp

Sterol regulatory element-binding protein (SREBP)-1c is now well established as a key transcription factor for the regulation of lipogenic enzyme genes such as FAS in hepatocytes. Meanwhile, the mechanisms of lipogenic gene regulation in adipocytes remain unclear. Here, we demonstrate that those in adipocytes are independent of SREBP-1c. In adipocytes, unlike in hepatocytes, the stimulation of SREBP-1c expression by liver X receptor agonist does not accompany lipogenic gene upregulation, although nuclear SREBP-1c protein is concomitantly increased, indicating that the activation process of SREBP-1c by the cleavage system is intact in adipocytes. Supportively, transcriptional activity of the mature form of SREBP-1c for the FAS promoter was negligible when measured by reporter analysis. As an underlying mechanism, accessibility of SREBP-1c to the functional elements was involved, because chromatin immunoprecipitation assays revealed that SREBP-1c does not bind to the functional SRE/E-box site on the FAS promoter in adipocytes. Moreover, genetic disruption of SREBP-1 did not cause any changes in lipogenic gene expression in adipose tissue. In summary, in adipocytes, unlike in hepatocytes, increments in nuclear SREBP-1c are not accompanied by transactivation of lipogenic genes; thus, SREBP-1c is not committed to the regulation of lipogenesis.

Supplementary key words sterol regulatory element-binding protein • lipogenesis • fatty acid synthase

Abbreviations: ACC, acetyl-coenzyme A carboxylase; ALLN, N-acetyl-leucyl-leucyl-norleucinal; ChIP, chromatin immunoprecipitation; LXR, liver X receptor; RXR, retinoid X receptor; SREBP, sterol regulatory element-binding protein

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