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.
Takeuchi
Yoshinori
Y
Laboratory of Molecular Physiology on Energy Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Yahagi
Naoya
N
Izumida
Yoshihiko
Y
Nishi
Makiko
M
Kubota
Midori
M
Teraoka
Yuji
Y
Yamamoto
Takashi
T
Matsuzaka
Takashi
T
Nakagawa
Yoshimi
Y
Sekiya
Motohiro
M
Iizuka
Yoko
Y
Ohashi
Ken
K
Osuga
Jun-ichi
J
Gotoda
Takanari
T
Ishibashi
Shun
S
Itaka
Keiji
K
Kataoka
Kazunori
K
Nagai
Ryozo
R
Yamada
Nobuhiro
N
Kadowaki
Takashi
T
Shimano
Hitoshi
H
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