MicroRNA-378 promotes hepatic inflammation and fibrosis via modulation of the NF-κB-TNFα pathway

• Published in: Journal of hepatology 2019-01, Vol.70 (1), p.87-96
• Main Authors: Zhang, Tianpeng, Hu, Junjie, Wang, Xiaomei, Zhao, Xiaoling, Li, Zhuoyu, Niu, Junqi, Steer, Clifford J., Zheng, Guohua, Song, Guisheng
• Format: Article
• Language: English
• Subjects: AMP; AMP-activated protein kinase; Animals; Biopsy; Cancer; Disease Models, Animal; Disease Progression; Fatty liver; Fibrosis; Gene Expression Regulation; Hepatitis - genetics; Hepatitis - metabolism; Hepatitis - pathology; High fat diet; Humans; Immunoblotting; Immunohistochemistry; Inflammation; Kinases; Liver - metabolism; Liver - pathology; Liver Cirrhosis - genetics; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver diseases; Male; Mice; Mice, Inbred C57BL; microRNA; MicroRNAs; MicroRNAs - biosynthesis; MicroRNAs - genetics; miRNA; NF-kappa B - metabolism; NF-κB protein; Non-alcoholic steatohepatitis; Obesity; Rodents; Signal Transduction; Therapeutic applications; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2018.08.026

[Display omitted] •Hepatic expression of miR-378 is significantly upregulated in fatty livers of mice and patients with NASH.•miR-378 is a potent inhibitor of AMPK signaling.•miR-378 facilitates an inflammatory pathway of NFκB-TNFα by targeting Prkag2.•miR-378 robustly promotes hepatic inflammation and fibrosis in dietary obese mice.•TNFα signaling is required for miR-378 to induce NASH progression. 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. 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. 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 γ 2 (AMPKγ2). AMPK signaling negatively regulates the NF-κB-TNFα 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-κB-TNFα. In contrast, miR-378 knockdown induced expression of Prkag2, increased sirtuin 1 activity and blocked the NF-κB-TNFα axis. Additionally, knockdown of increased Prkag2 offset the inhibitory effects of miR-378 inhibitor on the NF-κB-TNFα 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 TNFα signaling. Ablation of TNFα in miR-378-treated mice impaired the ability of miR-378 to facilitate hepatic inflammation and fibrosis, suggesting that TNFα signaling is required for miR-378 to promote NASH. MiR-378 plays a key role in the development of hepatic inflammation and fibrosis by positively regulating the NF-κB-TNFα axis. MiR-378 is a potential therapeutic target for the treatment of NASH. 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) rema