alexa Receptor-mediated uptake of low density lipoprotein reconstituted with 25-hydroxycholesteryl oleate suppresses 3-hydroxy-3-methylglutaryl-coenzyme A reductase and inhibits growth of human fibroblasts.
Bioinformatics & Systems Biology

Bioinformatics & Systems Biology

Journal of Glycomics & Lipidomics

Author(s): Krieger M, Goldstein JL, Brown MS

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Abstract The free and esterified cholesterols of plasma low density lipoprotein (LDL) were extracted with heptane and replaced with 25-hydroxycholesteryl oleate. The resulting particle, designated r-[25-HC oleate]LDL, bound to LDL receptors on human fibroblasts, was taken up by adsorptive endocytosis and was hydrolyzed in lysosomes in a manner similar to that of native LDL. The r-[25-HC oleate]LDL suppressed 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate:NADP(+) oxidoreductase (CoA-acylating), EC 1.1.1.34], the enzyme catalyzing the rate-limiting step in cholesterol biosynthesis. This suppression did not occur when lysosomal hydrolysis of r-[25-HC oleate]LDL was inhibited by chloroquine. When fibroblasts were incubated with r-[25-HC oleate]LDL in the absence of a source of cholesterol, the cells developed an abnormal morphology, their growth was inhibited, and the cells died. The toxic effects of r-[25-HC oleate]LDL were prevented when the growth medium was supplemented with cholesterol in ethanol or with mevalonate, the product of the reductase reaction. These data suggest that the toxicity of r-[25-HC oleate]LDL was due to its suppression of reductase, which in turn caused cellular cholesterol deficiency. The r-[25-HC oleate]LDL did not suppress reductase activity nor did it alter the growth or morphology of mutant fibroblasts lacking LDL receptors, which were obtained from a patient with homozygous familial hypercholesterolemia. These experiments demonstrate the feasibility of using reconstituted LDL to selectively deliver hydrophobic compounds other than typical cholesteryl esters to cells possessing LDL receptors.
This article was published in Proc Natl Acad Sci U S A and referenced in Journal of Glycomics & Lipidomics

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