Cited by 196MicroRNA in disease regulationLiver Disease Diagnosis and TreatmentLiver physiology and pathology

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

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Zhang, Tianpeng, Hu, Junjie, Wang, Xiaomei, Zhao, Xiaoling, Li, Zhuoyu, Niu, Junqi, Steer, Clifford J., Zheng, Guohua, Song, Guisheng·2019·Journal of Hepatology

DOI 10.1016/j.jhep.2018.08.026PMC PMC6554744

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Abstract

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 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.Conclusion 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.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.

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Authors: Zhang, T., Hu, J., Wang, X., Zhao, X., Li, Z., Niu, J., Steer, C. J., Zheng, G., & Song, G.
Affiliations: University of Minnesota (US)
Hubei University of Chinese Medicine (CN)
Jilin University (CN)
Shanxi University (CN)
Corresponding author: Zheng, Guohua
Song, Guisheng
ORCID: Zhang, Tianpeng
Hu, Junjie
Wang, Xiaomei
Zhao, Xiaoling
Li, Zhuoyu
Niu, Junqi
Steer, Clifford J.
Song, Guisheng
Venue: Journal of Hepatology
Publisher: Elsevier BV
Published: 2019-01
Volume: 70
Issue: 1
Pages: 87-96
ISSN: 0168-8278 (ISSN-L)
DOI: 10.1016/j.jhep.2018.08.026
PMC: PMC6554744
OpenAlex: W2890391525
Cited by: 196
References: 43
Citations by year: 2026: 15 · 2025: 23 · 2024: 34 · 2023: 23 · 2022: 37 · 2021: 43 · 2020: 14 · 2019: 7
FWCI: 4.82
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Journal of Hepatology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (R01 DK102601)
American Cancer Society (ISG-16-210-01-RMC)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords: miR-378, nonalcoholic steatohepatitis, liver inflammation, liver fibrosis, NF-κB signaling, TNF signaling, PRKAG2, AMPK, SIRT1, obesity, high-fat diet, microRNA, therapeutic target, hepatocellular carcinoma risk, liver-specific gene expression
MeSH terms: Animals, Biopsy, Disease Models, Animal, Gene Expression Regulation, Hepatitis, Humans, Immunohistochemistry, Liver, Liver Cirrhosis, Male, Mice, Inbred C57BL, Tumor Necrosis Factor-alpha, Immunoblotting, Signal Transduction, NF-kappa B, Disease Progression, MicroRNAs, Mice

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

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