A crucial role of sterol regulatory element-binding protein-1 in the regulation of lipogenic gene expression by polyunsaturated fatty acids

J Biol Chem. 1999 Dec 10;274(50):35840-4. doi: 10.1074/jbc.274.50.35840.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animal Feed
  • Animals
  • CCAAT-Enhancer-Binding Proteins*
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Chromans / pharmacology
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Diet
  • Dietary Carbohydrates
  • Dietary Fats, Unsaturated / pharmacology*
  • Dietary Proteins
  • Fenofibrate / pharmacology
  • Gene Expression Regulation, Enzymologic* / drug effects
  • Glycolysis
  • Humans
  • Liver / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism*
  • Rats
  • Stearoyl-CoA Desaturase / genetics
  • Sterol Regulatory Element Binding Protein 1
  • Thiazoles / pharmacology
  • Thiazolidinediones*
  • Transcription Factors*
  • Transcription, Genetic / drug effects
  • Troglitazone

Substances

  • CCAAT-Enhancer-Binding Proteins
  • Chromans
  • DNA-Binding Proteins
  • Dietary Carbohydrates
  • Dietary Fats, Unsaturated
  • Dietary Proteins
  • Nuclear Proteins
  • SREBF1 protein, human
  • Srebf1 protein, mouse
  • Srebf1 protein, rat
  • Sterol Regulatory Element Binding Protein 1
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factors
  • Stearoyl-CoA Desaturase
  • Troglitazone
  • Fenofibrate