Highlights
- •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.
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.
Graphical abstract
Graphical Abstract
Keywords
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Article info
Publication history
Published online: September 12, 2018
Accepted:
August 31,
2018
Received in revised form:
July 25,
2018
Received:
January 3,
2018
Identification
Copyright
© 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
