Polyunsaturated fatty acids decrease expression of promoters with sterol regulatory elements by decreasing levels of mature sterol regulatory element- binding protein

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.