Down-regulation of microRNA-375 regulates adipokines and inhibits inflammatory cytokines by targeting AdipoR2 in non-alcoholic fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD) has been considered as a multi-factorial metabolic syndrome. MicroRNA-375 (MiR-375) was significantly up-regulated in serum of NAFLD patients and the role of miR-375 was addressed as a putative biomarker of NAFLD progression. However, the specific function of miR-375 in the progression of NAFLD is still unclear and the molecular mechanisms underlying NAFLD have yet to be elucidated. Our study aimed at investigating the regulatory role of miR-375 in the molecular mechanisms of the pathogenic progression of NAFLD and to find out whether miR-375 regulates the expression level of adipokines and inflammatory cytokines in NAFLD. We found that miR-375 expression was increased in the serum of high fat diet (HFD)-feeding mice comparing to that in healthy controls, whereas the expression of Adiponectin receptor 2 (AdipoR2) was decreased in mice fed with HFD. Moreover, inhibiton of miR-375 up-regulated the expression of Adiponectin, inhibited the lipid accumulation and down-regulated both the level of Leptin and inflammatory cytokines including tumour necrosis factor (TNF)-α and interleukin (IL)-6 in palmiticacid (PA)-induced human hepatocellular carcinoma HepG2 cells. In addition, we also found that AdipoR2 was a target of miR-375 by binding directly to the 3'UTR of it. Of note, the reduced level of TNF-α, IL-6 as well as Leptin and the production of Adiponectin by miR-375 inhibitors was significantly reversed by silencing of AdipoR2 in PA-induced HepG2 cells. Our findings bring new insight into understanding the complex mechanisms underlying the pathogenesis of NAFLD and provide evidence that miR-375 might represent a novel therapeutic target for NAFLD.