FIGURE 1.

HIF pathway applied in liver fibrosis. During the development of liver fibrosis, oxygen mediated metabolic reprogramming occurs in a variety of cells. Abnormal lipid metabolism and activation of HIF in hepatocytes mediate the fibrotic pathway and the activation of HSC cells. Besides, activated HSCs occur in intracellular metabolic reprogramming, and they also mediate the metabolic transformation of other parenchymal cells. (A) In hepatocytes, activated HIF-1α or HIF-2α stimulates upregulation of Cxcl12 through converting latent TGF-β to active TGF-β. Succinate accumulates in hepatocytes due to enhanced fatty acid oxidation, which stabilized and activated HIF-1α through impairing PHDs. Expression of Cxcl12 and HIF-1α is involved in activation of HSCs. (B) In LSECs, PROX1 inhibites HIF‐1α ubiquitination via a deubiquitinase called USP19. A possible loop shows that HIF-1α induces PPARγ expression as a hypoxic response, then overexpressed PPARγ will inhibit HIF-1α transcription hypoxia as a negative feedback. (C) In activated HSCs, HIF-1 upregulates the GLUT1 and PKM2 expression in exosomes. Then these exosomes are absorbed by KCs, LSECs, and quiescent HSCs, which enhanced glycolysis of these nonparenchymal cells. (D) High-fat diet and Apoe knockout are common modeling methods of NAFLD. HIF-1 is also involved in metabolic disorder in the development of NAFLD to liver fibrosis. In this process, cholesterol load increased mitochondrial dysfunction and iNOS levels, which promoted HIF-1 stabilization and transcriptional activity. Then, the abnormal activation of HIF-1 promoted the production of iNOS and formed a malignant loop for fibrosis. Furthermore, HIF-1 is also involved in the circadian locomotor-related metabolic disorders in NAFLD. In CLOCK deficiency, HIF1α binds to the Cd36 promoter, promoting CD36 expression and uptake of fatty acids in the liver. High fat feeding and AP knockout mice are common modeling methods of NAFLD.