Polyunsaturated fatty acids selectively suppress sterol regulatory element-binding protein-1 through proteolytic processing and autoloop regulatory circuit

Yoshinori Takeuchi, Naoya Yahagi*, Yoshihiko Izumida, Makiko Nishi, Midori Kubota, Yuji Teraoka, Takashi Yamamoto, Takashi Matsuzaka, Yoshimi Nakagawa, Motohiro Sekiya, Yoko Iizuka, Ken Ohashi, Jun Ichi Osuga, Takanari Gotoda, Shun Ishibashi, Keiji Itaka, Kazunori Kataoka, Ryozo Nagai, Nobuhiro Yamada, Takashi KadowakiHitoshi Shimano

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

123 Scopus citations

Abstract

Sterol regulatory element-binding protein (SREBP)-1 is a key transcription factor for the regulation of lipogenic enzyme genes in the liver. Polyunsaturated fatty acids (PUFA) selectively suppress hepatic SREBP-1, but molecular mechanisms remain largely unknown. To gain insight into this regulation, we established in vivo reporter assays to assess the activities of Srebf1c transcription and proteolytic processing. Using these in vivo reporter assays, we showed that the primary mechanism for PUFA suppression of SREBP-1 is at the proteolytic processing level and that this suppression in turn decreases the mRNA transcription through lowering SREBP-1 binding to the SREBP-binding element on the promoter ("autoloop regulatory circuit"), although liver X receptor, an activator for Srebf1c transcription, is not involved in this regulation by PUFA. The mechanisms forPUFAsuppression of SREBP-1 confirm that the autoloop regulation for transcription is crucial for the nutritional regulation of triglyceride synthesis.

Original languageEnglish
Pages (from-to)11681-11691
Number of pages11
JournalJournal of Biological Chemistry
Volume285
Issue number15
DOIs
StatePublished - 2010/04/09

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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