Abstract
Misregulated microRNA network has been emerging as the main regulator in non-alcoholic fatty liver disease (NAFLD). The deregulation of miR-122-5p is associated with the liver disease. However, the specific role and molecular mechanism of miR-122-5p in NAFLD remain unclear. In this study, we have reported that the high-fat diet (HFD) or palmitic acid (PA) significantly upregulated the hepatic miR-122-5p expression in vivo and in vitro. Inhibition of miR-122-5p suppressed accumulation-induced inflammation of lipids and oxidative stress damage in PA-treated L02 cells and HFD-induced fatty liver. The effect of the miR-122-5p inhibitor on NAFLD did not depend on insulin resistance-mediated PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway but rather on the upregulation of its downstream FOXO3. Subsequently, we validated that miR-122-5p directly binds to the predicted 3′-UTR of FOXO3 to inhibit its gene expression. Conversely, silencing FOXO3 abolished the hepatic benefits of miR-122-5p inhibition to obese mice by decreasing the activity of antioxidant enzymes of superoxide dismutase (SOD). This study provides a novel finding that FOXO3 was the target gene of miR-122-5p to attenuate inflammatory response and oxidative stress damage in dietary-induced NAFLD. Our study provided evidence to reveal the physiological role of miR-122-5p in dietary-induced NAFLD.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is considered as a chronic progressive liver disorder that begins with simple hepatic steatosis and progresses to be non-alcoholic steatohepatitis, cirrhosis, and even liver cancer (Chiang et al, 2011)
Previous studies have implied that obese patients with NAFLD presented a significantly higher level of miR-122-5p in the liver (Akuta et al, 2016; Latorre et al, 2017), so we first sought to determine whether high-fat diet (HFD) increased hepatic miR-122-5p levels in mice
Misregulated miRNAs has been reported to be involved in NAFLD pathogenesis, such as hepatic inflammatory response, oxidative stress damage, and lipid accumulation (Castro et al, 2013; Yamada et al, 2013; Torres et al, 2018)
Summary
Non-alcoholic fatty liver disease (NAFLD) is considered as a chronic progressive liver disorder that begins with simple hepatic steatosis and progresses to be non-alcoholic steatohepatitis, cirrhosis, and even liver cancer (Chiang et al, 2011). Many misregulated microRNAs (miRNAs) in the liver have been identified from patients and dietary-induced murine obesity models with severe NAFLD. Some recent studies have demonstrated a potential role of miRNAs in the pathogenesis of NAFLD and insulin resistance (Cheng et al, 2016; Nie et al, 2017; Zhu et al, 2017). As the most abundant miRNAs are expressed in the liver, miR122-5p has been widely reported to participate in the regulation of lipid and cholesterol metabolisms, as well as the proliferation and differentiation of hepatocytes (Raitoharju et al, 2016). Recent studies have suggested that obese patients with NAFLD exhibited a higher miR-122-5p expression in the liver (Akuta et al, 2016; Latorre et al, 2017). The miR-122-5p function is not clear in NAFLD
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