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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.
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.
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