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J Biol Chem, Vol. 274, Issue 50, 35840-35844, December 10, 1999
From the Department of Metabolic Diseases, Faculty of Medicine,
University of Tokyo, Tokyo 113-8655, Japan
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.
A Crucial Role of Sterol Regulatory Element-binding Protein-1
in the Regulation of Lipogenic Gene Expression by Polyunsaturated Fatty
Acids*
,
*
This work was supported in part by Promotion of Fundamental
Studies in Health Science of the Organization for Pharmaceutical Safety
and Research and Health Sciences Research Grants (Research on Human
Genome and Gene Therapy) from the Ministry of Health and Welfare.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. 7-3-1 Hongo,
Bunkyo-ku, Tokyo, 113-8655, Japan. Tel.: 81-3-3815-5411 (ext. 33113); Fax: 81-3-5802-2955; E-mail: shimano-tky@umin.ac.jp.
¶
Present address: Division of Endocrinology and Metabolism,
Dept. of Internal Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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