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

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)5052-5056
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume75
Issue number10
DOIs
StatePublished - 1978

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this