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Journal of Lipid Research, Vol. 41, 1347-1355, August 2000
Copyright © 2000 by Lipid Research, Inc.

Original Article

In nonhepatic cells, cholesterol 7-hydroxylase induces the expression of genes regulating cholesterol biosynthesis, efflux, and homeostasis

Correspondence to: Roger A. Davis

CHO cells expressing the liver-specific gene product cholesterol-7-hydroxylase showed a 6-fold increase in the biosynthesis of [¹⁴C]cholesterol from [¹⁴C]acetate, as well as increased enzymatic activities of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and squalene synthase. Cells expressing cholesterol-7-hydroxylase contained less sterol response element-binding protein 1 (SREBP1) precursor, whereas the cellular content of mature SREBP1, as well as the mRNAs of cholesterol biosynthetic genes (HMG-CoA reductase and squalene synthase), were all increased 3-fold. Cells expressing cholesterol-7-hydroxylase displayed greater activities of luciferase reporters containing the SREBP-dependent promoter elements derived from HMG-CoA reductase and farnesyl diphosphate synthase, in spite of accumulating significantly more free and esterified cholesterol and 7-hydroxycholesterol. While cells expressing cholesterol-7-hydroxylase displayed increased SREBP-dependent transcription, sterol-mediated repression of SREBP-dependent transcription by LDL-cholesterol and exogenous oxysterols was similar in both cell types. Cells expressing cholesterol-7-hydroxylase displayed greater rates of secretion of cholesterol as well as increased expression of the ABC1 cassette protein mRNA. Adding 25-hydroxycholesterol to the culture medium of both cell types increased the expression of ABC1 cassette protein mRNA.

The combined data suggest that in nonhepatic CHO cells multiple regulatory processes sensitive to cellular sterols act independently to coordinately maintain cellular cholesterol homeostasis.—Spitsen, G. M., S. Dueland, S. K. Krisans, C. J. Slattery, J. H. Miyake, and R. A. Davis. In nonhepatic cells, cholesterol-7-hydroxylase induces the expression of genes regulating cholesterol biosynthesis, efflux, and homeostasis. J. Lipid Res. 2000. 41: 1347;–1355.

Supplementary key words: cholesterol, sterol regulation, oxysterols, 7-hydroxylase

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