Sterol regulatory element-binding protein (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

Advanced Biomedical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki 305-8575

Corresponding Author: 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 fatty acid synthase (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 (LXR) agonist does not accompany lipogenic gene up-regulation, although nuclear SREBP-1c protein is concomitantly elevated, indicating that the activation process of SREBP-1c by cleavage system is intact in adipocytes. Supportively, transcriptional activity of the mature form of SREBP-1c for 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 functional SRE/E-box site on FAS promoter in adipocytes. Moreover, genetic disruption of SREBP-1 did not cause any changes in the lipogenic gene expression in adipose tissue. In summary, in adipocytes unlike in hepatocytes, increment in nuclear SREBP-1c is not accompanied with transactivation of lipogenic genes, thus, SREBP-1c is not committed to regulation of lipogenesis.

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