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J Biol Chem, Vol. 273, Issue 40, 25537-25540, October 2, 1998
§,§¶,§,
, and§
From the Departments of Membrane physiology, plasma lipid levels, and
intracellular sterol homeostasis are regulated by both fatty acids and
cholesterol. Sterols regulate gene expression of key enzymes of
cholesterol and fatty acid metabolism through proteolysis of the sterol
regulatory element-binding protein (SREBP), which binds to sterol
regulatory elements (SRE) contained in promoters of these genes. We
investigated the effect of fatty acids on SRE-dependent
gene expression and SREBP. Consistent results were obtained in three
different cell lines (HepG2, Chinese hamster ovary, and CV-1)
transfected with SRE-containing promoters linked to the luciferase
expression vector. We show that micromolar concentrations of oleate and
other polyunsaturated fatty acids (C18:2-C22:6)
dose-dependently (0.075-0.6 mmol) decreased transcription
of SRE-regulated genes by 20-75%. Few or no effects were seen with
saturated free fatty acids. Fatty acid effects on
SRE-dependent gene expression were independent and additive to those of exogenous sterols. Oleate decreased levels of the mature
sterol regulatory element-binding proteins SREBP-1 and -2 and HMG-CoA
synthase mRNA. Oleate had no effect in sterol regulation defective
Chinese hamster ovary cells or in cells transfected with mutant
SRE-containing promoters. We hypothesize that unsaturated fatty acids
increase intracellular regulatory pools of cholesterol and thus affect
mature SREBP levels and expression of SRE-dependent genes.
Pediatrics and
¶ Physiology and the § Institute of Human Nutrition,
Columbia University College of Physicians and Surgeons, New York, New
York 10032 and the Department of Molecular Biology and
Biochemistry, University of California,
Irvine, California 92697-3900
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