Inhibition of cholesterol synthesis and esterification regulates high density lipoprotein interaction with isolated epithelial cells of human small intestine.
The effect of two inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, lovastatin and monacolin L, and an inhibitor of acyl coenzyme A:cholesterol acyltransferase (ACAT), Sandoz compound 58-035, on the interaction of 125I-labeled high density lipoprotein-3 (HDL3) with isolated human enterocytes was studied. Both HMG-CoA reductase inhibitors inhibited cholesterol synthesis and 125I-labeled HDL3 binding and degradation by enterocytes; a strong correlation between changes in cholesterol synthesis and interaction of 125I-labeled HDL3 with cells was observed. Lovastatin caused reduction of the apparent number of 125I-labeled HDL3 binding sites without affecting the binding affinity. No changes of cell cholesterol content were observed after incubation of cells with lovastatin. Mevalonic acid reversed the effect of lovastatin on 125I-labeled HDL3 binding. Lovastatin blocked up-regulation of the HDL receptor in response to loading of cells with nonlipoprotein cholesterol and modified cholesterol-induced changes of 125I-labeled HDL3 degradation. Lovastatin also reduced HDL-mediated efflux of endogenously synthesized cholesterol from enterocytes. The ACAT inhibitor caused a modest increase of 125I-labeled HDL3 binding to enterocytes and significantly decreased its degradation; both effects correlated with inhibition of cholesteryl ester synthesis. The results allow us to assume that the intracellular free cholesterol pool may play a key role in regulation of the HDL receptor.
Sviridov
D D
DD
Institute of Experimental Cardiology, National Cardiology Research Center, Moscow, USSR.
Pavlov
M Y
MY
Safonova
I G
IG
Repin
V S
VS
Smirnov
V N
VN
D000924:Anticholesteremic Agents / Q000494:pharmacology; D002648:Child; D002675:Child, Preschool; D002784:Cholesterol / Q000096:biosynthesis* / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism*; D004847:Epithelial Cells; D004848:Epithelium / Q000378:metabolism; D004951:Esterification; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007223:Infant; D007231:Infant, Newborn; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008148:Lovastatin / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D002785:Sterol O-Acyltransferase / Q000378:metabolism
D000924:Anticholesteremic Agents; D002788:Cholesterol Esters; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008075:Lipoproteins, HDL; D009281:Naphthalenes; C045375:monacolin L; D002784:Cholesterol; D008148:Lovastatin; D002785:Sterol O-Acyltransferase