MicroRNA-665-3p exacerbates nonalcoholic fatty liver disease in mice

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 3MODIFIER LETTER PRIME-untranslated region of fibronectin type III domain-containing 5 (FNDC5) to downregulate its expression and inactivated the downstream AMP-activated protein kinase alpha (AMPK alpha) 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/AMPK alpha pathway, and inhibiting miR-665-3p may provide novel therapeutic strategies to treat NAFLD.

Automated summary

The study suggests that miR-665-3p plays a significant role in exacerbating oxidative stress and inflammation in NAFLD. Inhibiting miR-665-3p could be a potential therapeutic strategy for preventing NAFLD progression.