Abnormal cholesterol metabolism in imipramine-treated fibroblast cultures. Similarities with Niemann-Pick type C disease.
Addition of low-density lipoprotein (LDL) to cholesterol-deprived human skin fibroblast cultures treated by imipramine at a 20 microM concentration induced a significant intracellular accumulation of unesterified cholesterol. Intracytoplasmic inclusions were already visible by histochemical filipin staining after 2 h of LDL uptake and were progressively mobilized towards the perinuclear region within 24 h. At this concentration of the drug, the rate of proteolytic 125I-LDL hydrolysis was similar in treated and untreated cells. Treated cells maintained in lipoprotein-deficient medium showed no abnormality, indicating the exogenous origin of the accumulated sterol. Further, the drug induced a drastic dose-dependent impairment of LDL-stimulated cholesterol esterification, not related to an inhibition of acyl CoA:cholesterol acyltransferase, and a significant delay in down-regulation of de novo cholesterol synthesis. However, imipramine did not affect 25-hydroxycholesterol-mediated regulation of the two latter processes. These results resemble those observed in Niemann-Pick type C disease and suggest an impaired mobilization of LDL-derived cholesterol in imipramine-treated cells.
Rodriguez-Lafrasse
C
C
Department of Biochemistry, INSERM U 189, Faculté de Médecine Lyon-Sud Oullins, France.
Rousson
R
R
Bonnet
J
J
Pentchev
P G
PG
Louisot
P
P
Vanier
M T
MT
D000085:Acetates / Q000378:metabolism; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000096:biosynthesis; D008078:Cholesterol, LDL / Q000378:metabolism*; D015536:Down-Regulation; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism; D007099:Imipramine / Q000494:pharmacology*; D007700:Kinetics; D009542:Niemann-Pick Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology
D000085:Acetates; D002788:Cholesterol Esters; D008078:Cholesterol, LDL; D006888:Hydroxycholesterols; C007997:25-hydroxycholesterol; D007099:Imipramine