We found induction of HIF-1α after alcohol feeding and demonstrated that hepatocyte-specific inhibition of HIF-1 prevented the alcohol-induced Acalabrutinib ic50 steatosis, suggesting

that HIF-1α alone can mediate alcohol-induced steatosis. This observation is somewhat different from the results of Rankin et al.,22 who recently described a dominant role for the HIF-2α isoform in hepatic lipid regulation using a scheme of cre-lox–mediated activation of HIF-1α or HIF-2α in hepatocytes; in that model, disruption of either HIF isoform in combination with pVHL knockout resulted in activation of the remaining isoform. Their findings, however, were in sharp contrast to work by Scortegagna et al.23 Alectinib concentration that demonstrated that adult HIF-2 knockout mice developed severe hepatic steatosis that could be reversed by treatment with a superoxide dismutase inhibitor. Kim et al., as well, found no significant contribution to hepatic lipid accumulation with a constitutively active mutant of HIF-2, despite finding a robust effect on angiogenesis. On the other hand, they demonstrated a mild HIF-1α–dependent effect on lipid accumulation.10 The different genetic techniques used to create specific gene expression or knockout in each of these studies may offer some explanation of the different results

each describes. Many of the genes involved in lipid homeostasis are regulated by HIFs.24, 25 However, it is yet to be dissected whether significant differences exist in the contribution of HIF-1α and HIF-2α in a given cell type and/or cell-specific effects. Our data suggest that in hepatocytes both in vivo and in vitro (in mice as well as in human cells), HIF-1α activation alone is sufficient to induce lipid click here accumulation. We explored the contribution of ADRP, a lipid droplet-associated surface protein that is regulated by HIF.21 ADRP has been shown to be up-regulated in human steatosis as well as in mice developing steatosis after a high-fat diet.26, 27 Here we report the novel observation that ADRP is up-regulated with chronic ethanol alone. We found further cooperative up-regulation of ADRP in WT mice after alcohol feeding and LPS

injection that correlated with HIF-1α induction. ADRP was up-regulated with constitutive HIF-1α expression but conversely, ADRP up-regulation with chronic ethanol and/or LPS injection was prevented in mice with hepatocyte-specific HIF-1α deletion. This suggested a mechanistic role for HIF-1α in ADRP induction and liver steatosis. Increasing evidence suggests that lipid accumulation is affected by proinflammatory stimuli. In support of this notion, the chemokine MCP-1 was recently shown to cause lipid accumulation in human hepatoma cells.8 We found a synergistic up-regulation of MCP-1 in the serum of chronic alcohol-fed, LPS-challenged mice suggesting that increased gut-derived LPS could amplify MCP-1 induction in ALD.