Figure 2

Pathways of HIF involvement in the Pathogenesis of Alcoholic Liver Disease Chronic alcohol causes increased gut permeability, which results in increased LPS entering the portal circulation. This stimulates TLR4 receptors in the hepatic macrophage, which in turn cause TNFα secretion via an NFκB, HIF1α dependent mechanism. LPS may also stimulate hepatic TLR4 to result in HIF1α activation (Nath, in submission.) Chronic alcohol increases results in an increase in HIF1α in whole liver, possibly mediated through the known effects of ethanol on increased metabolic demand, alteration in cellular redox state, and the creation of reactive oxygen species, all of which can increase HIF1α. HIF1α activation increases lipid accumulation. MCP-1 also increases lipid accumulation, and was shown to increase HIF1α in a hepatoma cell line in vitro.