Metabolomics Reveals the role of hypoxia‐inducible factors in hypoxia‐induced liver metabolic shift

Hypoxia‐inducible factor (HIF) is critical in the cellular adaptation to low cellular oxygen. A sustained increase in HIF signaling leads to spontaneous steatosis, inflammation and liver tumorigenesis. However, the metabolic responses and signaling networks regulated by HIFs in the liver are unclear. In the current study, serum from liver‐specific Von Hippel‐Lindau (Vhl)‐deficient mice overexpressing HIF was analyzed by metabolomics using LC‐MS. A dramatic decrease in metabolites involved in fatty acid β‐oxidation, which was correlated with the suppression of genes responsible for β‐oxidation, indicating a mitochondrial fatty acid oxidation defect. GC‐MS data revealed a sustained enrichment of lactate and alanine in serum of Vhl‐deficient mice. However, glutamine, an important energy substrate was robustly increased with these mice. These metabolomics data demonstrate that HIF is responsible for a metabolic shift from oxidative phosphorylation to glycolysis under hypoxia. In addition, many bile acids were found dramatically accumulated in Vhl‐deficient mice, indicating a disruption of liver bile acid metabolism. Taken together, these data reveal a central role for HIF in hepatic and systemic metabolic reprogramming under hypoxia and provide potential biomarkers for liver diseases. This study was funded by National Cancer Institute Intramural Program.