Hepatic miR-192-3p re-activation alleviates steatosis by targeting glucocorticoid receptor

Abstract Background and Aims The paradox of hepatic insulin resistance describes the inability for liver to respond to bioenergetics hormones in suppressing gluconeogenesis whilst maintaining lipid synthesis. Here, we report the deficiency of miR-192-3p (3p) in the livers of diabetic mice and its role in alleviating hepatic steatosis. Methods Conventional pre-miRNA stem-loop overexpression only boosts guiding strand (i.e. miR-192-5p) expression, we adopted an artificial AAV(DJ)-directed, RNA Pol III promoter driven miRNA hairpin construct for star strand-specific overexpression in the liver. Liver steatosis and insulin resistance markers were evaluated in primary hepatocytes, diabetic mice, and mice with excessive carbohydrate consumption. Results Functional loss of miR-192-3p in liver exacerbated hepatic microvesicular steatosis and insulin resistance in either diabetic mice or wild type mice with excessive fructose consumption. Liver-specific overexpression of miR-192-3p effectively halted hepatic steatosis and ameliorated insulin resistance in these mice models. Likewise, hepatocytes overexpressing miR-192-3p exhibited improved lipid accumulation, accompanied with decreases in lipogenesis and lipid accumulation-related transcripts. Mechanistically, glucocorticoid receptor (GCR, also known as NR3C1) was demonstrated to be negatively regulated by miR-192-3p. The effect of miR-192-3p on mitigating microvesicular steatosis was ablated by the re-activation of NR3C1. Conclusion The star strand miR-192-3p was an undermined glycerolipid regulator involved in controlling fat accumulation and insulin sensitivity in liver through blockade of hepatic GCR signalling; this miRNA may serve as a potential therapeutic option for the common co-mobility of diabetic mellitus and fatty liver disease.