8 The hypoxia-inducible factors (HIFs) are a family of heterodimeric transcription factors that promote a homeostatic transcriptional response to low oxygen tension. Mature HIF is composed of one of three isoforms of an alpha subunit (HIF-1α, HIF-2α, or HIF3α) and a beta subunit, the major isoform of
which is termed HIF-1β or the aryl-hydrocarbon receptor nuclear translocator (ARNT). Under conditions of normal oxygen tension, the alpha subunits of HIF are rapidly scaffolded on the Von-Hippel Lindau tumor suppressor protein, where they are hydroxylated and subsequently ubiquitinated and degraded. Under conditions of low oxygen tension, HIF alpha subunits escape hydroxylation
and dimerize with HIF-1β/ARNT, translocate to the nucleus and activate hypoxia response elements (HREs) in the genome.9 HIFs are named by their alpha subunit, with HIF-1 and HIF-2 having a wide, overlapping www.selleckchem.com/products/pifithrin-alpha.html but nonidentical set of transcriptional targets.10 In a recently described model, HIF1dPA, a mutant of HIF-1α construct in which the proline that is normally targeted for hydroxylation is mutated to alanine, enables tissue-specific constitutive activation of HIF.10 In the HIF-1α(Hep−/−) model, floxed exons of the native HIF-1α gene enable tissue-specific ablation of HIF activity.11 Recent investigation with the HIF1dPA model demonstrated that whereas activation of HIF-1 alone resulted in minimal lipid accumulation, and activation of HIF-2 Selleckchem EPZ6438 alone resulted in gross vascular changes without any appreciable increase in hepatic lipid, simultaneous activation of HIF-1 and HIF-2 results in a phenotype of hepatomegaly with macrovesicular lipid accumulation.10 However, the relationship of this phenotype to human diseases characterized by steatosis why (e.g., alcoholic steatosis or nonalcoholic fatty liver disease) remains to be elucidated. The role of HIFs in ALD is yet to be fully explored. Liver hypoxia has been documented in rats on a continuous ethanol diet, and some investigators
suggest that a process analogous to ischemia-reperfusion injury may be implicated.12-15 Others have postulated an increase in HIF-1α messenger RNA (mRNA) as a mechanism of ethanol-induced liver injury.16 However, the direct contribution of HIF-1 to alcoholic liver injury is unknown. We hypothesized that HIF-1α protein, mRNA, and downstream gene activation would be up-regulated in the livers of mice after chronic ethanol feeding, and that modifying HIF expression in hepatocytes might affect the progression of ALD. In order to dissect the contribution of HIF-1α to ALD, we used cre-lox mouse models of hepatocyte-specific HIF-1α activation (HIF1dPA) as well as hepatocyte-specific HIF-1α deletion (HIF-1α(Hep−/−)).