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, 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.
Laboratory of Molecular Physiology on Energy Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Yoshinori
Y
Takeuchi
Naoya
N
Yahagi
Yoshihiko
Y
Izumida
Makiko
M
Nishi
Midori
M
Kubota
Yuji
Y
Teraoka
Takashi
T
Yamamoto
Takashi
T
Matsuzaka
Yoshimi
Y
Nakagawa
Motohiro
M
Sekiya
Yoko
Y
Iizuka
Ken
K
Ohashi
Jun-ichi
J
Osuga
Takanari
T
Gotoda
Shun
S
Ishibashi
Keiji
K
Itaka
Kazunori
K
Kataoka
Ryozo
R
Nagai
Nobuhiro
N
Yamada
Takashi
T
Kadowaki
Hitoshi
H
Shimano
D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
D005231:Fatty Acids, Unsaturated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides