trans-Chalcone prevents insulin resistance and hepatic inflammation and also promotes hepatic cholesterol efflux in high-fat diet-fed rats: modulation of miR-34a-, miR-451-, and miR-33a-related pathways.

Abstract

Insulin resistance and inflammation are strongly linked to non-alcoholic fatty liver disease (NAFLD) as a feature of the metabolic syndrome. Furthermore, the role of dysregulation of miR-34a, miR-451, and miR-33a in pathogenesis and progression of NAFLD has been identified. trans-Chalcone is a simple chalcone with anti-diabetic and anti-inflammatory activities. However, to the best of our knowledge, miRNA-dependent mechanisms of these protective effects under pathologic conditions are not understood. Thus, this study, for the first time, aimed to evaluate the effects of trans-Chalcone on miR-34a, miR-451, and miR-33a signaling pathways in the liver of high-fat (HF) emulsion-fed rats. To this aim, twenty-one rats were randomly and equally divided into three groups: control, which was gavaged with 10% tween 80; HF, which was gavaged with HF emulsion and 10% tween 80; and HF + trans-Chalcone (HF + TC), which was gavaged with HF emulsion and trans-Chalcone. Then, circulating levels of glucose and insulin were measured and used for the calculation of HOMA-IR. Hepatic expression levels of miR-34a, miR-451, miR-33a, SIRT1, and ABCA1 and also protein levels of ABCA1 and IL-8 were assayed. In this study, trans-chalcone increased hepatic cholesterol efflux and prevented insulin resistance and liver inflammation in HF emulsion-fed rats. These protective effects were modulated through the down-regulation of miR-34a and its associated elevation of SIRT1, the up-regulation of miR-451 which was associated with a reduction in IL-8, and the inhibition of miR-33a which was related to the elevation of ABCA1 in the liver of HF emulsion-fed rats. Therefore, trans-Chalcone exerts its beneficial effects by targeting hepatic miR-34a-, miR-451-, and miR-33a-related pathways.