title: Modified low density lipoproteins decrease the activity and expression of lysosomal acid lipase in human endothelial and smooth muscle cells.
abstract: Lysosomal acid lipase (LAL), the only lysosomal enzyme involved in the hydrolysis of LDL-cholesteryl esters, is a key regulator of cellular cholesterol and fatty acid homeostasis and its deficiency contributes to the pathophysiology of various diseases. In this study, we questioned whether oxidized or glycated LDL, a common occurrence in atherosclerosis and diabetes, affect the activity and expression of LAL in vascular endothelial cells (EC) and smooth muscle cells (SMC). LAL activity and expression were assayed in cultured human EC and SMC exposed to oxidized LDL (oxLDL), (±)9-hydroxyoctadecadienoic acid-cholesteryl ester (HODE), glycated LDL (gLDL), or native LDL (nLDL) as control, in the presence or absence of LXR or PPAR-gamma agonists. We found that LAL activity and expression were significantly down regulated by oxLDL and HODE in EC, and by gLDL in SMC. The LXR agonist T0901317 reversed the decreased LAL expression in modified LDL- or HODE-exposed EC (P < 0.001) and in gLDL-exposed SMC, whereas PPAR-gamma agonist rosiglitazone induced a low effect only in EC. In conclusion, modified LDL down regulates LAL expression in human EC and SMC by a process involving the LXR signaling pathway. This is the first demonstration that modified LDL modulate LAL expression, in a cell specific manner.
authors.affiliation: Institute of Cellular Biology and Pathology N. Simionescu, 8, B. P. Hasdeu Street, PO Box 14-35, 050568 Bucharest, Romania. ina.heltianu@icbp.ro
authors.forename: Constantina
authors.initials: C
authors.lastname: Heltianu
authors.forename: Alexandra
authors.initials: A
authors.lastname: Robciuc
authors.forename: Gabriela
authors.initials: G
authors.lastname: Botez
authors.forename: Claudia
authors.initials: C
authors.lastname: Musina
authors.forename: Camelia
authors.initials: C
authors.lastname: Stancu
authors.forename: Anca V
authors.initials: AV
authors.lastname: Sima
authors.forename: Maya
authors.initials: M
authors.lastname: Simionescu
mesh_terms: D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D017127:Glycation End Products, Advanced; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D000071518:Liver X Receptors; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology*; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D002787:Sterol Esterase / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; D000093844:Glycated Proteins
chemical_list: D017127:Glycation End Products, Advanced; D006845:Hydrocarbons, Fluorinated; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D002787:Sterol Esterase; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C031797:glycated lipoproteins, LDL; D000093844:Glycated Proteins; C099252:oxidized low density lipoprotein