| First Author | Wang X | Year | 2019 |
| Journal | Hepatology | Volume | 69 |
| Issue | 2 | Pages | 545-563 |
| PubMed ID | 30102772 | Mgi Jnum | J:318897 |
| Mgi Id | MGI:6850913 | Doi | 10.1002/hep.30215 |
| Citation | Wang X, et al. (2019) Macrophage-Specific Hypoxia-Inducible Factor-1alpha Contributes to Impaired Autophagic Flux in Nonalcoholic Steatohepatitis. Hepatology 69(2):545-563 |
| abstractText | Inflammatory cell activation drives diverse cellular programming during hepatic diseases. Hypoxia-inducible factors (HIFs) have recently been identified as important regulators of immunity and inflammation. In nonalcoholic steatohepatitis (NASH), HIF-1alpha is upregulated in hepatocytes, where it induces steatosis; however, the role of HIF-1alpha in macrophages under metabolic stress has not been explored. In this study, we found increased HIF-1alpha levels in hepatic macrophages in methionine-choline-deficient (MCD) diet-fed mice and in macrophages of patients with NASH compared with controls. The HIF-1alpha increase was concomitant with elevated levels of autophagy markers BNIP3, Beclin-1, LC3-II, and p62 in both mouse and human macrophages. LysM(Cre) HIF(dPA) fl/fl mice, which have HIF-1alpha levels stabilized in macrophages, showed higher steatosis and liver inflammation compared with HIF(dPA) fl/fl mice on MCD diet. In vitro and ex vivo experiments reveal that saturated fatty acid, palmitic acid (PA), both induces HIF-1alpha and impairs autophagic flux in macrophages. Using small interfering RNA-mediated knock-down and overexpression of HIF-1alpha in macrophages, we demonstrated that PA impairs autophagy via HIF-1alpha. We found that HIF-1alpha mediates NF-kappaB activation and MCP-1 production and that HIF-1alpha-mediated impairment of macrophage autophagy increases IL-1beta production, contributing to MCD diet-induced NASH. Conclusion: Palmitic acid impairs autophagy via HIF-1alpha activation in macrophages. HIF-1alpha and impaired autophagy are present in NASH in vivo in mouse macrophages and in human blood monocytes. We identified that HIF-1alpha activation and decreased autophagic flux stimulate inflammation in macrophages through upregulation of NF-kappaB activation. These results suggest that macrophage activation in NASH involves a complex interplay between HIF-1alpha and autophagy as these pathways promote proinflammatory overactivation in MCD diet-induced NASH. |
