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MicroRNA-665-3p exacerbates nonalcoholic fatty liver disease in mice
Yuanjie Yu1,2, Tian Tian1,2, Shiyun Tan1,2
1Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China.
Abstract:
Oxidative stress and chronic inflammation are major culprits of nonalcoholic fatty liver disease (NAFLD). MicroRNA-665-3p (miR-665-3p) is implicated in regulating inflammation and oxidative stress; however, its role and molecular basis in NAFLD remain elusive. Herein, we measured a significant upregulation of miR-665-3p level in the liver and primary hepatocytes upon high fat diet (HFD) or 0.5 mmol/L palmitic acid plus 1.0 mmol/L oleic acid stimulation, and the elevated miR-665-3p expression aggravated oxidative stress, inflammation and NAFLD progression in mice. In contrast, miR-665-3p inhibition by the miR-665-3p antagomir significantly prevented HFD-induced oxidative stress, inflammation and hepatic dysfunction in vivo. Manipulation of miR-665-3p in primary hepatocytes also caused similar phenotypic alterations in vitro. Mechanistically, we demonstrated that miR-665-3p directly bound to the 3'-untranslated region of fibronectin type III domain-containing 5 (FNDC5) to downregulate its expression and inactivated the downstream AMP-activated protein kinase alpha (AMPKα) pathway, thereby facilitating oxidative stress, inflammation and NAFLD progression. Our findings identify miR-665-3p as an endogenous positive regulator of NAFLD via inactivating FNDC5/AMPKα pathway, and inhibiting miR-665-3p may provide novel therapeutic strategies to treat NAFLD.
Insights
MicroRNA-665-3p (miR-665-3p) promotes nonalcoholic fatty liver disease (NAFLD) by increasing oxidative stress and inflammation. Inhibiting miR-665-3p offers a potential therapeutic strategy for NAFLD treatment.
Area of Science:
- Hepatology
- Molecular Biology
- Biochemistry
Background:
- Nonalcoholic fatty liver disease (NAFLD) pathogenesis involves oxidative stress and chronic inflammation.
- The precise role of microRNA-665-3p (miR-665-3p) in NAFLD remains unclear.
- miR-665-3p is known to influence inflammatory and oxidative stress pathways.
Purpose of the Study:
- To investigate the role and molecular mechanisms of miR-665-3p in NAFLD.
- To determine if miR-665-3p levels are altered in NAFLD conditions.
- To explore the therapeutic potential of targeting miR-665-3p for NAFLD.
Main Methods:
- Quantified miR-665-3p expression in mouse liver and primary hepatocytes under high-fat diet (HFD) or fatty acid stimulation.
- Administered miR-665-3p antagomirs in vivo to assess effects on HFD-induced NAFLD.
- Utilized in vitro cell culture models to manipulate miR-665-3p levels and observe phenotypic changes.
- Investigated the direct interaction between miR-665-3p and fibronectin type III domain-containing 5 (FNDC5) mRNA using 3'-untranslated region (3'-UTR) assays.
- Assessed the impact of miR-665-3p on the AMP-activated protein kinase alpha (AMPKα) signaling pathway.
Main Results:
- miR-665-3p expression was significantly upregulated in NAFLD models (HFD and fatty acid stimulation).
- Elevated miR-665-3p aggravated oxidative stress, inflammation, and NAFLD progression in mice.
- Inhibition of miR-665-3p using antagomirs ameliorated HFD-induced hepatic oxidative stress, inflammation, and dysfunction.
- In vitro manipulation of miR-665-3p in hepatocytes mirrored the in vivo findings.
- Mechanistically, miR-665-3p directly targets FNDC5, downregulating its expression and inactivating the AMPKα pathway.
Conclusions:
- miR-665-3p acts as a positive regulator in NAFLD progression.
- The mechanism involves the downregulation of FNDC5 and subsequent inactivation of the FNDC5/AMPKα pathway.
- Inhibiting miR-665-3p presents a promising novel therapeutic strategy for NAFLD.
