Hepatic miR-192-3p reactivation alleviates steatosis by targeting glucocorticoid receptor
Publication in refereed journal


摘要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.

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.

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.

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.
著者WANG Zhangting, MIU Kai-Kei, ZHANG Xueyan, WAN Tsz-Yau Angel, LU Gang, CHEUNG Hoi-Hung, LEE Heung-Man, KONG Pik-Shan Alice, CHAN Chung-Ngor Juliana, CHAN Wai-Yee
期刊名稱JHEP Reports
出版社Elsevier B.V.
關鍵詞hepatic steatosis, diabetes mellitus, microRNA, glucocorticoid receptor, transcription repressor, high carbohydrate consumption

上次更新時間 2021-14-06 於 00:11