■肝胰岛素抵抗的悖论描述了肝脏在抑制糖异生同时维持脂质合成方面无法对生物能激素做出反应。这里,我们报道了糖尿病小鼠肝脏中miR-192-3p的缺乏及其在减轻肝脏脂肪变性中的作用。
■因为常规的pre-microRNA(miRNA)茎环过表达仅增强引导链(即miR-192-5p)表达,我们采用了人造AAV(DJ)指导,RNAPolIII启动子驱动的miRNA发夹构建体在肝脏中星形链特异性过表达。在原代肝细胞中评估肝脂肪变性和胰岛素抵抗标志物,患有糖尿病的老鼠,和过量摄入碳水化合物的小鼠。
■肝脏中miR-192-3p的功能丧失加剧了糖尿病小鼠或果糖消耗过多的野生型小鼠的肝微泡脂肪变性和胰岛素抵抗。miR-192-3p的肝脏特异性过表达在这些小鼠模型中有效地阻止了肝脂肪变性并改善了胰岛素抵抗。同样,过表达miR-192-3p的肝细胞表现出改善的脂质积累,伴随着脂肪生成和脂质积累相关转录物的减少。机械上,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miR-192-3p负调控。miR-192-3p对减轻微泡脂肪变性的作用通过NR3C1的再激活而消除。
■星链miR-192-3p是一种被破坏的甘油酯调节剂,通过阻断肝脏GCR信号传导来控制肝脏中的脂肪积累和胰岛素敏感性;该miRNA可能作为糖尿病和脂肪肝疾病共同迁移的潜在治疗选择。
■星链microRNA(miRNA)物种的潜在调节活性已被大大低估。在这项研究中,我们研究了被忽视的星链miRNA(miR-192-3p)在调节糖尿病小鼠和过量碳水化合物摄入小鼠肝脏中的肝脂肪变性和胰岛素信号中的作用和机制.
UNASSIGNED: 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.
UNASSIGNED: As conventional pre-microRNA (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, mice with diabetes, and mice with excessive carbohydrate consumption.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.