Restoration of a regulatory response to low density lipoprotein in acid lipase deficient human fibroblasts

M. S. Brown, M. K. Sobhani, G. Y. Brunschede, J. L. Goldstein

Research output: Contribution to journalArticle

34 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3277-3286
Number of pages10
JournalJournal of Biological Chemistry
Volume251
Issue number11
StatePublished - 1976

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Cholesterol Esters
Fibroblasts
Lipase
LDL Lipoproteins
Restoration
Cholesterol Ester Storage Disease
Sterol Esterase
Hyperlipoproteinemia Type II
Lipoproteins
Oxidoreductases
Monolayers
Chemical activation
LDL Receptors
Homozygote
Hydrolases
Culture Media
Metabolism
Cell Culture Techniques
Plasmas
Defects

ASJC Scopus subject areas

  • Biochemistry

Cite this

Restoration of a regulatory response to low density lipoprotein in acid lipase deficient human fibroblasts. / Brown, M. S.; Sobhani, M. K.; Brunschede, G. Y.; Goldstein, J. L.

In: Journal of Biological Chemistry, Vol. 251, No. 11, 1976, p. 3277-3286.

Research output: Contribution to journalArticle

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