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Volume 272, Number 31, Issue of August 1, 1997 pp. 19351-19358
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Coordinate Regulation of Lipogenesis, the Assembly and Secretion of Apolipoprotein B-containing Lipoproteins by Sterol Response Element Binding Protein 1

(Received for publication, February 24, 1997, and in revised form, May 27, 1997)

From the Mammalian Cell and Molecular Biology Laboratory, Department of Biology and Molecular Biology Institute, San Diego State University, San Diego, California 92182-0057

Stable plasmid-driven expression of the liver-specific gene product cholesterol 7-hydroxylase (7-hydroxylase) was used to alter the cellular content of transcriptionally active sterol response element binding protein 1 (SREBP1). As a result of stable expression of 7-hydroxylase, individual single cell clones expressed varying amounts of mature SREBP1 protein. These single cell clones provided an opportunity to identify SREBP1-regulated genes that may influence the assembly and secretion of apoB-containing lipoproteins. Our results show that in McArdle rat hepatoma cells, which normally do not express 7-hydroxylase, plasmid-driven expression of 7-hydroxylase results in the following: 1) a linear relationship between (i) the cellular content of mature SREBP1 and 7-hydroxylase protein, (ii) the relative expression of 7-hydroxylase mRNA and the mRNA's encoding the enzymes regulating fatty acid, i.e. acetyl-CoA carboxylase and sterol synthesis, i.e. HMG-CoA reductase, (iii) the relative expression of 7-hydroxylase mRNA and microsomal triglyceride transfer protein mRNA, a gene product that is essential for the assembly and secretion of apoB-containing lipoproteins; 2) increased synthesis of all lipoprotein lipids (cholesterol, cholesterol esters, triglycerides, and phospholipids); and 3) increased secretion of apoB100 without any change in apoB mRNA. Cells expressing 7-hydroxylase contained significantly less cholesterol (both free and esterified). The increased cellular content of mature SREBP1 and increased secretion of apoB100 were concomitantly reversed by 25-hydroxycholesterol, suggesting that the content of mature SREBP1, known to be decreased by 25-hydroxycholesterol, mediates the changes in the lipoprotein assembly and secretion pathway that are caused by 7-hydroxylase. These data suggest that several steps in the assembly and secretion of apoB-containing lipoproteins by McArdle hepatoma cells may be coordinately linked through the cellular content of mature SREBP1.

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