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

• DOI: 10.1194/jlr.m700033-jlr200
• Publication Date: 2007-04-25T02:33:00Z
• Authors: 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; Hitoshi Shimano
• Keywords: Male; 0301 basic medicine; Hydrocarbons, Fluorinated; Receptors, Cytoplasmic and Nuclear; QD415-436; Biochemistry; Mice; 03 medical and health sciences; Adipocytes; Animals; Rats, Wistar; lipogenesis; Cells, Cultured; Liver X Receptors; fatty acid synthase; Sulfonamides; Orphan Nuclear Receptors; Rats; DNA-Binding Proteins; Mice, Inbred C57BL; Gene Expression Regulation; Hepatocytes; Fatty Acid Synthases; Sterol Regulatory Element Binding Protein 1; sterol regulatory element-binding protein; Protein Processing, Post-Translational

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.