Pregnane X receptor-agonists down-regulate hepatic ATP-binding cassette transporter A1 and scavenger receptor class B type I.
Pregnane X receptor (PXR) is the molecular target for a wide variety of endogenous and xenobiotic compounds. It regulates the expression of genes central to the detoxification (cytochrome P-450 enzymes) and excretion (xenobiotic transporters) of potentially harmful compounds. The aim of the present investigation was to determine the role of PXR in regulation of high-density lipoprotein (HDL) cholesterol metabolism by studying its impact on ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-BI) expression in hepatocytes. ABCA1 and SR-BI are major factors in the exchange of cholesterol between cells and HDL. Expression analyses were performed using Western blotting and quantitative real time RT-PCR. Luciferase reporter gene assays were used to measure promoter activities. Total cholesterol was measured enzymatically after lipid extraction (Folch's method). The expression of ABCA1 and SR-BI was inhibited by the PXR activators rifampicin and lithocholic acid (LCA) in HepG2 cells and pregnenolone 16alpha-carbonitrile (PCN) in primary rat hepatocytes. Thus, PXR appears to be a regulator of hepatic cholesterol transport by inhibiting genes central to cholesterol uptake (SR-BI) and efflux (ABCA1).
Sporstøl
Marita
M
Programme for Cell Biology, Department of Molecular Biosciences, University of Oslo, Oslo, Norway. marita.sporstol@imbv.uio.no
Tapia
German
G
Malerød
Lene
L
Mousavi
Seyed Ali
SA
Berg
Trond
T
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D018955:CD36 Antigens; D002478:Cells, Cultured; D017931:DNA Primers; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D051116:Receptors, Scavenger; D011987:Receptors, Steroid / Q000819:agonists*; D051122:Scavenger Receptors, Class B
D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; D017931:DNA Primers; D000077297:Pregnane X Receptor; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; D051116:Receptors, Scavenger; D011987:Receptors, Steroid; C495125:Scarb1 protein, rat; D051122:Scavenger Receptors, Class B