Regulatory Role of Endothelial PHD2 in the Hepatic Steatosis

BACKGROUND/AIMS: Liver disease is a leading cause of high mortality and morbidity worldwide. The aim of the present study is to investigate the regulatory role of prolyl hydroxylase-2 (PHD2)-hypoxia-inducible factor-2α (HIF-2α) axis on nonalcoholic fatty liver disease (NAFLD) and to explore the potential mechanisms by which endothelial (EC)-specific PHD2 deficiency regulates hepatic steatosis and fibrosis. METHODS: In the endothelial-specific PHD2 knockout (PHD2(EC)KO) mouse fed with normal diet or high fat diet (HFD), liver lipid accumulation and fibrosis were measured by Oil Red O and Masson trichrome staining. The fat and body weight (FW/BW) ratio and glucose tolerance were measured. The expression of HIF-2α, atrial natriuretic peptide (ANP), angiopoietin-2 (Ang-2), and transforming growth factor-β (TGF-β) were analyzed by western blot analysis. RESULTS: The steatosis and fibrosis were significantly increased in the PHD2(EC)KO mice. FW/BW ratio was significantly increased in the PHD2(EC)KO mice. Moreover, knockout of endothelial PHD2 resulted in an impairment of glucose tolerance in mice. Western blot analysis showed that the expression of HIF-2α in liver tissues was not significantly increased. Interestingly, the expression of ANP was decreased, and Ang-2 and TGF-β levels were significantly increased in the liver of PHD2(EC)KO mice. The FW/BW ratio was also significantly increased in the PHD2(EC)KO mice fed with HFD for 16 weeks. Feeding HFD resulted in a significant increase in hepatic steatosis in the control PHD2(f/f) mice, but did not further enhance hepatic steatosis in the PHD2(EC)KO mice. CONCLUSIONS: We concluded that the endothelial PHD2 plays a critical role in hepatic steatosis and fibrosis, which may be involved in the regulation of ANP and Ang-2/TGF-β signaling pathway, but not the HIF-2α expression.