PPARγ activates ABCA1 gene transcription but reduces the level of ABCA1 protein in HepG2 cells.
Synthesis of ABCA1 protein in liver is necessary for high-density lipoproteins (HDL) formation in mammals. Nuclear receptor PPARγ is known as activator of ABCA1 expression, but details of PPARγ-mediated regulation of ABCA1 at both transcriptional and post-transcriptional levels in hepatocytes have not still been well elucidated. In this study we have shown, that PPARγ activates ABCA1 gene transcription in human hepatoma cells HepG2 through increasing of LXRβ binding with promoter region of ABCA1 gene. Treatment of HepG2 cells with PPARγ agonist GW1929 leads to dissociation of LXRβ from ABCA1/LXRβ complex and to nuclear translocation of this nuclear receptor resulting in reduction of ABCA1 protein level 24h after treatment. Inhibition of protein kinases MEK1/2 abolishes PPARγ-mediated dissociation of LXRβ from ABCA1/LXRβ complex, but does not block PPARγ-dependent down-regulation of ABCA1 protein in HepG2 cells. These data suggest that PPARγ may be important for regulation of the level of hepatic ABCA1 protein and indicate the new interplays between PPARγ, LXRβ and MEK1/2 in regulation of ABCA1 mRNA and protein expression.
Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, 197376 St. Petersburg, Russia. denis@iem.sp.ru
Denis A
DA
Mogilenko
Vladimir S
VS
Shavva
Ella B
EB
Dizhe
Sergey V
SV
Orlov
Andrej P
AP
Perevozchikov
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism*; D001577:Benzophenones / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000378:metabolism*; D000071518:Liver X Receptors; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001577:Benzophenones; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D014443:Tyrosine; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C120099:GW 1929