Liver X receptor and retinoic X receptor agonists modulate the expression of genes involved in lipid metabolism in human endothelial cells.
The cooperation of liver X receptors (LXRs) alpha and beta, and retinoic X receptor (RXR) modulate the expression of several genes involved in lipid metabolism in hepatocyte and macrophages. Using cDNA microarray technology, we have shown previously that several of these genes are also expressed in endothelial cells. In the present study, we investigated whether the activation of LXR and RXR affects the expression of genes involved in lipid metabolism in human endothelial cells. Relative expression of ABCA-1, CETP, SR-B1, EL, LPL, PLTP, ApoE and LDLR was investigated in HUVECs, human fibroblasts (hFB) and HepG2 cells by quantitative real-time PCR. For CETP and EL mRNA expression, the results were HUVECs > hFB > HEPG2; for PLTP, LDLR and LPL: hFB > HUVECs > HEPG2; for SR-B1 and ApoE: HEPG2 > HUVECs > hFB; and for ABCA-1 HEPG2: > hFB > HUVECs. Incubation of HUVECs with LXR agonists as 22-(R)-hydroxycholesterol (22-(R)-HC) or T0901317-induced ABCA1 (20.1- and 17.8-fold), LPL (3.46- and 7.03-fold) and CETP (6.34- and 3.98-fold) expression; EL, LDLR and SR-B1 expression was induced only upon incubation with T0901317 (2.40-, 2.83- and 2.19-fold, respectively) while 22-(R)-HC had no effect on EL and SR-B1 expression (0.8- and 0.9-fold) and decreased LDLR expression (0.4-fold). No effect of either 22-(R)-HC or T0901317 on PLTP and ApoE expression was observed. The RXR agonist, 9-cis retinoic acid (9CRA) alone induced the expression of CETP, LPL and SR-B1 (2.8-, 8.2- and 2.4-fold). No effect of 9CRA on ABCA-1, EL, PLTP, ApoE, and LDLR expression was observed. Association of 9CRA with 22-(R)-HC or T0901317 increased the expression of CETP and LPL while no effect on ABCA-1 or LDLR was observed. Activation of LXRs and RXRs in endothelial cells represents a new target of LXR and RXR agonist in the arterial wall. Modulation of gene expression in the endothelium should be taken into account when studying the effects of LXR and RXR agonists on lipid metabolism in the arterial wall.
Norata
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GD
Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy.
Ongari
M
M
Uboldi
P
P
Pellegatta
F
F
Catapano
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AL
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000077556:Alitretinoin; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D053480:Cholesterol Ester Transfer Proteins; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D006888:Hydroxycholesterols / Q000494:pharmacology; D050356:Lipid Metabolism; D008071:Lipoprotein Lipase / Q000235:genetics / Q000378:metabolism; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D047488:Retinoid X Receptors / Q000819:agonists* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000077556:Alitretinoin; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D006845:Hydrocarbons, Fluorinated; D006888:Hydroxycholesterols; D008071:Lipoprotein Lipase; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D047488:Retinoid X Receptors; D051122:Scavenger Receptors, Class B; D013449:Sulfonamides; D014212:Tretinoin; C577836:ABCA1 protein, human; C506642:CETP protein, human; C495124:SCARB1 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C003585:22-hydroxycholesterol