Polyunsaturated Fatty Acids Selectively Suppress Sterol Regulatory Element-binding Protein-1 through Proteolytic Processing and Autoloop Regulatory Circuit

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,...

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Bibliographic Details
Published in:The Journal of biological chemistry 2010-04, Vol.285 (15), p.11681-11691
Main Authors: Takeuchi, Yoshinori, Yahagi, Naoya, Izumida, Yoshihiko, Nishi, Makiko, Kubota, Midori, Teraoka, Yuji, Yamamoto, Takashi, Matsuzaka, Takashi, Nakagawa, Yoshimi, Sekiya, Motohiro, Iizuka, Yoko, Ohashi, Ken, Osuga, Jun-ichi, Gotoda, Takanari, Ishibashi, Shun, Itaka, Keiji, Kataoka, Kazunori, Nagai, Ryozo, Yamada, Nobuhiro, Kadowaki, Takashi, Shimano, Hitoshi
Format: Article
Language:English
Subjects:
Animals
Cell Line
Cell Nucleus - metabolism
Fatty Acid
Fatty Acids, Unsaturated - metabolism
Gene Expression Regulation
Gene Regulation
Humans
Lipids
Lipogenesis
Liver
Liver - metabolism
Liver X Receptors
Male
Mice
Mice, Inbred ICR
Orphan Nuclear Receptors - metabolism
Polyunsaturated Fatty Acids
Promoter Regions, Genetic
Promoters
Protein Binding
Sterol Regulatory Element Binding Protein 1 - metabolism
Sterol Regulatory Element-binding Protein
Transcription Factors
Triglycerides - metabolism
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Summary: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 for PUFA suppression of SREBP-1 confirm that the autoloop regulation for transcription is crucial for the nutritional regulation of triglyceride synthesis.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M109.096107