Wang Zhangting, Miu Kai-Kei, Zhang Xueyan, Wan Angel Tsz-Yau, Lu Gang, Cheung Hoi-Hung, Lee Heung-Man, Kong Alice Pik-Shan, Chan Juliana Chung-Ngor, Chan Wai-Yee
School of Biomedical Sciences, Faculty of Medicine, Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
Department of Gynecology, Women's Hospital, School of Medicine, Zhejiang University, Zhejiang, China.
JHEP Rep. 2020 Sep 6;2(6):100179. doi: 10.1016/j.jhepr.2020.100179. eCollection 2020 Dec.
BACKGROUND & 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 in the livers of mice with diabetes and its role in alleviating hepatic steatosis.
As conventional pre-microRNA (miRNA) stem-loop overexpression only boosts guiding strand ( 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, mice with diabetes, and mice with excessive carbohydrate consumption.
Functional loss of miR-192-3p in liver exacerbated hepatic micro-vesicular steatosis and insulin resistance in either mice with diabetes 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 nuclear receptor subfamily 3, group C, member 1 [NR3C1]) was demonstrated to be negatively regulated by miR-192-3p. The effect of miR-192-3p on mitigating micro-vesicular steatosis was ablated by the reactivation 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.
The potential regulatory activity of star strand microRNA (miRNA) species has been substantially underestimated. In this study, we investigate the role and mechanism of an overlooked star strand miRNA (miR-192-3p) in regulating hepatic steatosis and insulin signalling in the livers of mice with diabetes and mice under excessive carbohydrate consumption.
肝脏胰岛素抵抗的矛盾现象指的是肝脏在抑制糖异生的同时维持脂质合成时，无法对生物能量激素作出反应。在此，我们报告糖尿病小鼠肝脏中miR-192-3p的缺乏及其在减轻肝脏脂肪变性中的作用。
由于传统的前体微小RNA（miRNA）茎环过表达仅能提高引导链（miR-192-5p）的表达，我们采用了一种人工腺相关病毒（DJ）定向、RNA聚合酶III启动子驱动的miRNA发夹构建体，用于在肝脏中进行星链特异性过表达。在原代肝细胞、糖尿病小鼠和碳水化合物摄入过量的小鼠中评估肝脏脂肪变性和胰岛素抵抗标志物。
肝脏中miR-192-3p的功能丧失加剧了糖尿病小鼠或果糖摄入过量的野生型小鼠的肝脏微泡性脂肪变性和胰岛素抵抗。miR-192-3p的肝脏特异性过表达有效地阻止了这些小鼠模型中的肝脏脂肪变性，并改善了胰岛素抵抗。同样，过表达miR-192-3p的肝细胞表现出脂质积累改善，同时脂肪生成和脂质积累相关转录本减少。从机制上讲，糖皮质激素受体（GCR，也称为核受体亚家族3，C组，成员1 [NR3C1]）被证明受到miR-192-3p的负调控。NR3C1的重新激活消除了miR-192-3p对减轻微泡性脂肪变性的作用。
星链miR-192-3p是一种未被充分认识的甘油脂质调节剂，通过阻断肝脏GCR信号传导参与控制肝脏中的脂肪积累和胰岛素敏感性；这种miRNA可能是糖尿病和脂肪肝疾病常见共同发病机制的潜在治疗选择。
星链微小RNA（miRNA）物种的潜在调节活性被大大低估了。在本研究中，我们研究了一种被忽视的星链miRNA（miR-192-3p）在调节糖尿病小鼠和碳水化合物摄入过量小鼠肝脏中的肝脏脂肪变性和胰岛素信号传导中的作用及机制。
