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-1 beta and INF alpha. Recently, two novel additional (alternative) promoters for human apoA-I gene have been identified. Nothing is known about the role of alternative promoters in TNF alpha-mediated downregulation of apoA-I gene. In this article we report for the first time about the different effects of TNF alpha on two alternative promoters of human apoA-I gene. Stimulation of HepG2 cells by TNF alpha 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 TNF alpha. The MEK1/2-ERK1/2 cascade and nuclear receptors PPAR alpha and LXRs are important for TNF alpha-mediated apoA-I promoter switching. (C) 2010 Elsevier Inc. All rights reserved.