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MicroRNA-378 promotes hepatic inflammation and fibrosis via modulation of the NF-κB-TNFα pathway
Open accessAbstract
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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“The most overexpressed miRNA in patients’ cells was the miR-378-3p, which is considered a modulator of the epithelial-to-mesenchymal transition and is associated with inflammation and fibrosis through the positive modulation of NF-kB and TNFα pathways [167,168].”
From Cellular and Molecular Mechanisms in the Pathogenesis of Classical, Vascular, and Hypermobile Ehlers‒Danlos Syndromes (2019) · cites this paper as [168]
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Metadata
- 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
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 70
- Issue
- 1
- Pages
- 87-96
- ISSN
- 0168-8278 (ISSN-L)
- 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
- 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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