Effect of TNFalpha on activities of different promoters of human apolipoprotein A-I gene.
Human apolipoprotein A-I (ApoA-I) is a major structural and functional protein component of high-density lipoproteins. The expression of the apolipoprotein A-I gene (apoA-I) in hepatocytes is repressed by pro-inflammatory cytokines such as IL-1beta and TNFalpha. Recently, two novel additional (alternative) promoters for human apoA-I gene have been identified. Nothing is known about the role of alternative promoters in TNFalpha-mediated downregulation of apoA-I gene. In this article we report for the first time about the different effects of TNFalpha on two alternative promoters of human apoA-I gene. Stimulation of HepG2 cells by TNFalpha leads to activation of the distal alternative apoA-I promoter and downregulation of the proximal alternative and the canonical apoA-I promoters. This effect is mediated by weakening of the promoter competition within human apoA-I 5'-regulatory region (apoA-I promoter switching) in the cells treated by TNFalpha. The MEK1/2-ERK1/2 cascade and nuclear receptors PPARalpha and LXRs are important for TNFalpha-mediated apoA-I promoter switching.
Orlov
Sergey V
SV
Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, 197376 St. Petersburg, Russia. serge@iem.sp.ru
Mogilenko
Denis A
DA
Shavva
Vladimir S
VS
Dizhe
Ella B
EB
Ignatovich
Irina A
IA
Perevozchikov
Andrej P
AP
D016632:Apolipoprotein A-I / Q000235:genetics*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D000071518:Liver X Receptors; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D016632:Apolipoprotein A-I; D000071518:Liver X Receptors; D016328:NF-kappa B; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D014409:Tumor Necrosis Factor-alpha; D020929:Mitogen-Activated Protein Kinase Kinases