| First Author | Zhang T | Year | 2019 |
| Journal | J Hepatol | Volume | 70 |
| Issue | 1 | Pages | 87-96 |
| PubMed ID | 30218679 | Mgi Jnum | J:295670 |
| Mgi Id | MGI:6454207 | Doi | 10.1016/j.jhep.2018.08.026 |
| Citation | Zhang T, et al. (2019) MicroRNA-378 promotes hepatic inflammation and fibrosis via modulation of the NF-kappaB-TNFalpha pathway. J Hepatol 70(1):87-96 |
| abstractText | BACKGROUND & AIMS: The progression of hepatosteatosis to non-alcoholic steatohepatitis (NASH) is a critical step in the pathogenesis of hepatocellular cancer. However, the underlying mechanism(s) for this progression is essentially unknown. This study was designed to determine the role of miR-378 in regulating NASH progression. METHODS: We used immunohistochemistry, luciferase assays and immunoblotting to study the role of miR-378 in modulating an inflammatory pathway. Wild-type mice kept on a high-fat diet (HFD) were injected with miR-378 inhibitors or a mini-circle expression system containing miR-378, to study loss and gain-of functions of miR-378. RESULTS: MiR-378 expression is increased in livers of dietary obese mice and patients with NASH. Further studies revealed that miR-378 directly targeted Prkag2 that encodes AMP-activated protein kinase gamma 2 (AMPKgamma2). AMPK signaling negatively regulates the NF-kappaB-TNFalpha inflammatory axis by increasing deacetylase activity of sirtuin 1. By targeting Prkag2, miR-378 reduced sirtuin 1 activity and facilitated an inflammatory pathway involving NF-kappaB-TNFalpha. In contrast, miR-378 knockdown induced expression of Prkag2, increased sirtuin 1 activity and blocked the NF-kappaB-TNFalpha axis. Additionally, knockdown of increased Prkag2 offset the inhibitory effects of miR-378 inhibitor on the NF-kappaB-TNFalpha axis, suggesting that AMPK signaling mediates the role of miR-378 in facilitating this inflammatory pathway. Liver-specific expression of miR-378 triggered the development of NASH and fibrosis by activating TNFalpha signaling. Ablation of TNFalpha in miR-378-treated mice impaired the ability of miR-378 to facilitate hepatic inflammation and fibrosis, suggesting that TNFalpha signaling is required for miR-378 to promote NASH. CONCLUSION: MiR-378 plays a key role in the development of hepatic inflammation and fibrosis by positively regulating the NF-kappaB-TNFalpha axis. MiR-378 is a potential therapeutic target for the treatment of NASH. LAY SUMMARY: The recent epidemic of obesity has been associated with a sharp rise in the incidence of non-alcoholic fatty liver disease (NAFLD). However, the underlying mechanism(s) remains poorly described and effective therapeutic approaches against NAFLD are lacking. The results establish that microRNA-378 facilitates the development of hepatic inflammation and fibrosis and suggests the therapeutic potential of microRNA-378 inhibitor for the treatment of NAFLD. |
