title: A crucial role of sterol regulatory element-binding protein-1 in the regulation of lipogenic gene expression by polyunsaturated fatty acids.
abstract: Dietary polyunsaturated fatty acids (PUFA) are negative regulators of hepatic lipogenesis that exert their effects primarily at the level of transcription. Sterol regulatory element-binding proteins (SREBPs) are transcription factors responsible for the regulation of cholesterol, fatty acid, and triglyceride synthesis. In particular, SREBP-1 is known to play a crucial role in the regulation of lipogenic gene expression in the liver. To explore the possible involvement of SREBP-1 in the suppression of hepatic lipogenesis by PUFA, we challenged wild-type mice and transgenic mice overexpressing a mature form of SREBP-1 in the liver with dietary PUFA. In the liver of wild-type mice, dietary PUFA drastically decreased the mature, cleaved form of SREBP-1 protein in the nucleus, whereas the precursor, uncleaved form in the membranes was not suppressed. The decreases in mature SREBP-1 paralleled those in mRNAs for lipogenic enzymes such as fatty acid synthase and acetyl-CoA carboxylase. In the transgenic mice, dietary PUFA did not reduce the amount of transgenic SREBP-1 protein, excluding the possibility that PUFA accelerated the degradation of mature SREBP-1. The resulting sustained expression of mature SREBP-1 almost completely canceled the suppression of lipogenic gene expression by PUFA in the SREBP-1 transgenic mice. These results demonstrate that the suppressive effect of PUFA on lipogenic enzyme genes in the liver is caused by a decrease in the mature form of SREBP-1 protein, which is presumably due to the reduced cleavage of SREBP-1 precursor protein.
authors.affiliation: Department of Metabolic Diseases, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Yahagi
authors.forename: H
authors.initials: H
authors.lastname: Shimano
authors.forename: A H
authors.initials: AH
authors.lastname: Hasty
authors.forename: M
authors.initials: M
authors.lastname: Amemiya-Kudo
authors.forename: H
authors.initials: H
authors.lastname: Okazaki
authors.forename: Y
authors.initials: Y
authors.lastname: Tamura
authors.forename: Y
authors.initials: Y
authors.lastname: Iizuka
authors.forename: F
authors.initials: F
authors.lastname: Shionoiri
authors.forename: K
authors.initials: K
authors.lastname: Ohashi
authors.forename: J
authors.initials: J
authors.lastname: Osuga
authors.forename: K
authors.initials: K
authors.lastname: Harada
authors.forename: T
authors.initials: T
authors.lastname: Gotoda
authors.forename: R
authors.initials: R
authors.lastname: Nagai
authors.forename: S
authors.initials: S
authors.lastname: Ishibashi
authors.forename: N
authors.initials: N
authors.lastname: Yamada
mesh_terms: D000821:Animal Feed; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D004032:Diet; D004040:Dietary Carbohydrates; D004042:Dietary Fats, Unsaturated / Q000494:pharmacology*; D004044:Dietary Proteins; D011345:Fenofibrate / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006019:Glycolysis; D006801:Humans; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D013230:Stearoyl-CoA Desaturase / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D000077288:Troglitazone
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D002839:Chromans; D004268:DNA-Binding Proteins; D004040:Dietary Carbohydrates; D004042:Dietary Fats, Unsaturated; D004044:Dietary Proteins; D009687:Nuclear Proteins; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D013230:Stearoyl-CoA Desaturase; D000077288:Troglitazone; D011345:Fenofibrate