Hypoxia and hypoxia inducible factors: diverse roles in liver diseases

Abstract

Hypoxia has been shown to have a role in the pathogenesis of several forms of liver disease. The hypoxia inducible factors (HIFs) are a family of evolutionarily conserved transcriptional regulators that affect a homeostatic response to low oxygen tension and have been identified as key mediators of angiogenesis, inflammation, and metabolism. In this review we summarize the evidence for a role of HIFs across a range of hepatic pathophysiology. We describe regulation of the HIFs and review investigations that demonstrate a role for HIFs in the development of liver fibrosis, activation of innate immune pathways, hepatocellular carcinoma, as well as other liver diseases in both human disease as well as murine models.

Figure 1

Under conditions of normoxia, HIF alpha subunits are rapidly hydroxylated at proline and asparagine residues by hydroxylase enzymes. Hydroxylation of HIF1α and assembly on a protein scaffold consisting of the VHL tumor suppressor, along with other co-factors, results in the rapid ubiquitination of the alpha subunit and subsequent degradation by the proteasome. Conversely, in conditions of hypoxia, HIF alpha subunits escape degradation and are free to dimerize with the binding partner, the Aryl Hydrocarbon Nuclear Translocator (ARNT). The HIF heterodimer is named by the alpha subunit (hence, HIF1α-ARNT heterodimer is the active HIF1 transcription factor) which translocates to the nucleus and affects transcription of target genes, typically by binding to a hypoxia response element in the upstream promoter region of the target gene. CBP/P300 and other cofactors may be implicated in HIF transcription. Other pathways of HIF regulation have been described in detail elsewhere.

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.