Effect of TNFα on activities of different promoters of human apolipoprotein A-I gene

• Published in: Biochemical and biophysical research communications 2010-07, Vol.398 (2), p.224-230
• Main Authors: Orlov, Sergey V., Mogilenko, Denis A., Shavva, Vladimir S., Dizhe, Ella B., Ignatovich, Irina A., Perevozchikov, Andrej P.
• Format: Article
• Language: English
• Subjects: Alternative transcription; Apolipoprotein A-I; HDLs; LXR; MEK1/2; PPARα; TNFα
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2010.06.064

► TNFα stimulates the distal alternative promoter of human apoA-I gene. ► TNFα acts by weakening of promoter competition within apoA-I gene (promoter switching). ► MEK1/2 and nuclear receptors PPARα and LXRs take part in apoA-I promoter switching. 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-1β and TNFα. Recently, two novel additional (alternative) promoters for human apoA-I gene have been identified. Nothing is known about the role of alternative promoters in TNFα-mediated downregulation of apoA-I gene. In this article we report for the first time about the different effects of TNFα on two alternative promoters of human apoA-I gene. Stimulation of HepG2 cells by TNFα 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 TNFα. The MEK1/2-ERK1/2 cascade and nuclear receptors PPARα and LXRs are important for TNFα-mediated apoA-I promoter switching.