title: Restoration of a regulatory response to low density lipoprotein in acid lipase-deficient human fibroblasts.
abstract: Previous studies have shown that cultured fibroblasts derived from patients with genetic defects in lysosomal acid lipase (i. e. the Wolman Syndrome and Cholesteryl Ester Storage Disease) are defective in their ability to hydrolyze the cholesteryl esters contained in plasma low density lipoprotein (LDL). As a result, these mutant cells show a reduced responsiveness to the regulatory actions of LDL, as evidenced by a decreased LDL-mediated suppression of the activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase and by a decreased LDL-mediated activation of cellular cholesteryl ester formation. In the current studies, the Wolman Syndrome and Cholesteryl Ester Storage Disease cells were grown in the same Petri dish with mutant fibroblasts derived from a patient with the homozygous form of Familial Hypercholesterolemia. Whereas pure monolayers of either the Familial Hypercholesterolemia cells (lacking cell surface LDL receptors) or the acid lipase-deficient cells (lacking cholesteryl ester hydrolase activity) responded poorly to LDL, the mixed monolayers developed lipoprotein responsiveness as measured by an enhancement of both LDL-mediated suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and LDL-mediated stimulation of cholesteryl ester formation. This effect was shown to result from the release of the lysosomal acid lipase from the Familial Hypercholesterolemia homozygote cells into the culture medium and its subsequent uptake by the acid lipase-deficient cells. The acquisition of this acid lipase activity enhanced the ability of the Wolman Syndrome and Cholesteryl Ester Storage Disease cells to respond to the lipoprotein by suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase and activation of cellular cholesteryl ester formation. These data emphasize the importance of the lysosomal acid lipase in the cellular metabolism of LDL cholesteryl esters and, in addition, demonstrate that delivery of this enzyme to genetically deficient cells can enhance the regulatory response to the lipoprotein.
mesh_terms: D001665:Binding Sites; D001693:Biological Transport, Active; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D007700:Kinetics; D008049:Lipase / Q000172:deficiency* / Q000378:metabolism; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D009829:Oleic Acids / Q000378:metabolism; D011485:Protein Binding; D002787:Sterol Esterase / Q000378:metabolism
chemical_list: D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D009829:Oleic Acids; D002787:Sterol Esterase; D008049:Lipase