The liver is a central organ that metabolizes excessive nutrients for storage in the form of glycogen and lipids and supplies energy-producing substrates to the peripheral tissues to maintain their function, even under starved conditions. These processes require a considerable amount of oxygen, which causes a steep oxygen gradient throughout the hepatic lobules. Alcohol consumption and/or excessive food intake can alter the hepatic metabolic balance drastically, which can precipitate fatty liver disease, a major cause of chronic liver diseases worldwide, ranging from simple steatosis, through steatohepatitis and hepatic fibrosis, to liver cirrhosis. Altered hepatic metabolism and tissue remodeling in fatty liver disease further disrupt hepatic oxygen homeostasis, resulting in severe liver hypoxia. As master regulators of adaptive responses to hypoxic stress, hypoxia-inducible factors (HIFs) modulate various cellular and organ functions, including erythropoiesis, angiogenesis, metabolic demand, and cell survival, by activating their target genes during fetal development and also in many disease conditions such as cancer, heart failure, and diabetes. In the past decade, it has become clear that HIFs serve as key factors in the regulation of lipid metabolism and fatty liver formation. This review discusses the molecular mechanisms by which hypoxia and HIFs regulate lipid metabolism in the development and progression of fatty liver disease.

Adaptive responses to hypoxia regulate hepatic lipid metabolism, but their consequences in nonalcoholic fatty liver disease (NAFLD) are largely unknown. Here, we show that hypoxia inducible factor-1 (HIF-1), a key determinant of hypoxic adaptations, prevents excessive hepatic lipid accumulation in the progression of NAFLD. When exposed to a choline-deficient diet (CDD) for 4 weeks, the loss of hepatic Hif-1α gene accelerated liver steatosis with enhanced triglyceride accumulation in the liver compared to wild-type (WT) livers. Expression of genes involved in peroxisomal fatty acid oxidation was suppressed significantly in CDD-treated WT livers, whereas this reduction was further enhanced in Hif-1α-deficient livers. A lack of induction and nuclear accumulation of lipin1, a key regulator of the PPARα/PGC-1α pathway, could be attributed to impaired peroxisomal β-oxidation in Hif-1α-deficient livers. The lipin1-mediated binding of PPARα to the acyl CoA oxidase promoter was markedly reduced in Hif-1α-deficient mice exposed to a CDD. Moreover, forced Lipin1 expression restored the aberrant lipid accumulation caused by Hif-1α deletion in cells incubated in a choline-deficient medium. These results strongly suggest that HIF-1 plays a crucial role in the regulation of peroxisomal lipid metabolism by activating the expression and nuclear accumulation of lipin1 in NAFLD.

Acetaminophen (APAP)‐induced liver injury is closely associated with acute hepatic inflammation. Hypoxia‐inducible factor‐1 (HIF‐1) is activated during immunological processes and regulates gene expressions in various types of immune cells. Although HIF‐1 controls the differentiation and functions of conventional T cells in chronic inflammation, the pathological importance of HIF‐1 in innate‐like T cells during acute inflammation remains unknown. Here, we investigated the role of HIF‐1 in innate‐like γδ T cells during APAP‐induced acute liver injury. In response to APAP administration, T‐cell‐specific Hif‐1α gene knockout mice sustained severe liver damage compared to wild‐type control mice but without any impacts on the initial hepatic insult. This severe liver damage was accompanied by excessive neutrophil infiltration into the liver, increased serum interleukin (IL)‐17A levels, and increased hepatic expressions of C‐X‐C chemokine ligand (Cxcl) 1 and Cxcl2. Neutrophil depletion and IL‐17A neutralization completely abolished the aggravated phenotypes in T‐cell‐specific Hif‐1α gene knockout mice. Loss of the Hif‐1α gene enhanced the aberrant accumulation of IL‐17A‐producing innate‐like γδ T cells in the affected liver with no apparent effects on their IL‐17A‐producing ability. Adoptive transfer of Hif‐1α‐deficient splenic γδ T cells into recombination activating gene 2 (Rag2)‐deficient mice aggravated APAP‐induced liver injury with increased neutrophil accumulation in the liver compared to that of wild‐type γδ T cells. Furthermore, Hif‐1α‐deficient γδ T cells selectively showed aberrantly enhanced migratory ability. This ability was totally abolished by treatment with the mitochondrial adenosine triphosphate synthase inhibitor oligomycin. Conclusion: Deletion of Hif‐1α gene in T cells aggravates APAP‐induced acute inflammatory responses by enhancing aberrant innate‐like γδ T‐cell recruitment, thereby increasing excessive neutrophil infiltration into the liver. (Hepatology Communications 2018;2:571‐581)