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 hypoxia inducible factors 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.

Chronic alcohol causes hepatic steatosis and liver hypoxia. Hypoxia-regulated Hypoxia-inducible factor 1-α, (HIF1α) may regulate liporegulatory genes but the relationship of HIF1 to steatosis remains unknown. We investigated HIF1α in alcohol-induced hepatic lipid accumulation. Alcohol administration resulted in steatosis, increased liver triglyceride levels and serum ALT suggesting liver injury in WT mice. There was increased hepatic HIF1α mRNA, protein and DNA-binding activity in alcohol-fed mice compared to controls. Mice engineered with hepatocyte-specific HIF1 activation (HIF1dPA) had increased HIF1α mRNA, protein, and DNA-binding activity, and alcohol feeding in HIF1dPA mice increased hepatomegaly and hepatic triglyceride compared to WT. In contrast, hepatocyte-specific deletion of HIF1α (HIF-1α(Hep-/-), protected mice from alcohol- and LPS-induced liver damage, serum ALT elevation, hepatomegaly and lipid accumulation. HIF-1α(Hep-/-), WT, and HIF1dPA mice had equally suppressed levels of PPARα mRNA after chronic ethanol, while the HIF target, ADRP, was upregulated in WT, but not in HIF-1α(Hep-/-) ethanol fed/LPS challenged mice. The chemokine, MCP-1, was cooperatively induced by alcohol feeding and LPS in WT but not in HIF-1α(Hep-/-) mice. Using Huh7 hepatoma cells in vitro, we found that MCP-1 treatment induced lipid accumulation and increased HIF1α protein expression as well as DNA-binding activity. SiRNA inhibition of HIF1α prevented MCP-1-induced lipid accumulation suggesting a mechanistic role for HIF1α in hepatocyte lipid accumulation. Conclusions Alcohol feeding results in lipid accumulation in hepatocytes involving HIF1α activation. The alcohol-induced chemokine, MCP-1, triggers lipid accumulation in hepatocytes via HIF1α activation, suggesting a mechanistic link between inflammation and hepatic steatosis in alcoholic liver disease.

Alcoholic liver disease (ALD) features increased hepatic exposure to bacterial lipopolysaccharide (LPS). Toll-like receptor-4 (TLR4) recognizes LPS and activates signaling pathways depending on MyD88 or TRIF adaptors. We previously showed that MyD88 is dispensable in ALD. TLR4 induces Type I interferons (IFNs) in an MyD88-independent manner that involves interferon regulatory factor-3 (IRF3). We fed alcohol or control diets to wild-type (WT) and IRF3 knock-out (KO) mice, and to mice with selective IRF3 deficiency in liver parenchymal and bone marrow-derived cells. Whole-body IRF3-KO mice were protected from alcohol-induced liver injury, steatosis, and inflammation. In contrast to WT or bone marrow-specific IRF3-KO mice, deficiency of IRF3 only in parenchymal cells aggravated alcohol-induced liver injury, associated with increased proinflammatory cytokines, lower antiinflammatory cytokine interleukin 10 (IL-10), and lower Type I IFNs compared to WT mice. Coculture of WT primary murine hepatocytes with liver mononuclear cells (LMNC) resulted in higher LPS-induced IL-10 and IFN-b, and lower tumor necrosis factor alpha (TNF-a) levels compared to LMNC alone. Type I IFN was important because cocultures of hepatocytes with LMNC from Type I IFN receptor KO mice showed attenuated IL-10 levels compared to control cocultures from WT mice. We further identified that Type I IFNs potentiated LPSinduced IL-10 and inhibited inflammatory cytokine production in both murine macrophages and human leukocytes, indicating preserved cross-species effects. These findings suggest that liver parenchymal cells are the dominant source of Type I IFN in a TLR4/IRF3-dependent manner. Further, parenchymal cell-derived Type I IFNs increase antiinflammatory and suppress proinflammatory cytokines production by LMNC in paracrine manner. Conclusion: Our results indicate that IRF3 activation in parenchymal cells and resulting type I IFNs have protective effects in ALD by way of modulation of inflammatory functions in macrophages. These results suggest potential therapeutic targets in ALD. (HEPATOLOGY 2011;53:649-660)

Our results show that the Nalp3 inflammasome is upregulated and activated in the liver in response to LPS stimulation.

The severe donor liver shortage, high cost, and complexity of orthotopic liver transplantation have prompted the search for alternative treatment strategies for end-stage liver disease, which would require less donor material, be cheaper, and less invasive. Hepatic tissue engineering encompasses several approaches to develop adjunct internal liver support methods, such as hepatocyte transplantation and implantable hepatocyte-based devices, as well as temporary extracorporeal liver support techniques, such as bioartificial liver assist devices. Many tissue engineered liver support systems have passed the "proof of principle" test in preclinical and clinical studies; however, they have not yet been found sufficiently reliably effective for routine clinical use. In this review we describe, from an engineering perspective, the progress and remaining challenges that must be resolved in order to develop the next generation of implantable and extracorporeal devices for adjunct or temporary liver assist. (Liver