41, 42 A seminal study in the field identified centrilobular injury

as a consequence of hepatic oxygen demand in alcohol-fed rats that were briefly exposed to low atmospheric oxygen tension, and were able to demonstrate protection against this effect with the coadministration of the thioamide antihyperthyroid drug propylthiouracil.41 The diverse effects of chronic ethanol on cellular signaling, cellular metabolism, and organ physiology has been reviewed elsewhere.43 The development of hypoxia in alcohol-exposed liver has also been reviewed elsewhere.44 Over three decades ago, exposure of thin liver slices to acute ethanol was reported to increase oxygen consumption.45 Acute ethanol causes a rapid increase in liver metabolism, including rapid induction of alcohol detoxifying enzymes and hepatic oxygen consumption within 2-3 hours.46 More recently, CAL-101 concentration acute ethanol was found to result in increased areas of staining using the hypoxia-specific marker pimonidazole; this effect appeared to be at least partially dependent on selleck chemicals functional hepatic Kupffer cells, and was also apparent in a model of chronic ethanol treatment.47, 48 Recent gene array data from ethanol-fed and pair-fed mice demonstrated up-regulation of multiple genes in the glycolytic pathway, as well as genes in lipid metabolic pathways in the livers of chronically

alcohol fed mice.49 Although not explored in that publication, most, if not all of these genes may be regulated by HIF1α. An earlier report suggested an up-regulation of HIF1α messenger RNA (mRNA) in the livers of chronic alcoholics.50 One group offered some data to indicate that HIF1α mRNA is cyclically regulated

with the urinary alcohol cycle in a model on continuous, intragastric ethanol feeding.51 More recently, in the hypercholesterolemic Ketotifen ApoE(−/−) mouse, ethanol significantly increased HIF1α protein in liver, and a synergistic up-regulation with tobacco smoke was observed.52 Our own recent work has demonstrated that chronic alcohol administration increased HIF activation in the liver and that increased hepatic steatosis in the setting of alcohol developed in an HIF-dependent manner.53 It has been well established that alcoholic liver disease proceeds in part through a combination of prolonged metabolic insult coupled with activation of signaling through innate immune mechanisms. Given the role of HIFs in innate immunity, as described further below, it is quite possible that the contribution of HIFs to alcoholic liver disease proceeds both through pathways of innate immunity as well as through pathways in the hepatocyte, including hepatic lipid accumulation. A schematic illustrating the convergence of innate immune pathways with HIF1α in an experimental model of steatohepatitis is given in Fig. 2.