Du Xiliang, Yang Yuchen, Xu Chuang, Peng Zhicheng, Zhang Min, Lei Lin, Gao Wenwen, Dong Yuhao, Shi Zhen, Sun Xudong, Wang Zhe, Li Xiaobing, Li Xinwei, Liu Guowen
Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China.
College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China.
Oncotarget. 2017 Aug 24;8(53):91362-91378. doi: 10.18632/oncotarget.20523. eCollection 2017 Oct 31.
The contributions of altered post-transcriptional gene silencing to the development of metabolic disorders remain poorly understood thus far. The objective of this study was to evaluate the roles of miR-181a in the regulation of hepatic glucose and lipid metabolism. MiR-181a is abundantly expressed in the liver, and we found that blood and hepatic miR-181a levels were significantly increased in patients and dairy cows with non-alcoholic fatty liver disease, as well as in high-fat diet and ob/ob mice. We determined that sirtuin1 is a target of miR-181a. Moreover, we found that hepatic sirtuin1 and peroxisome proliferator-activated receptor-γ coactivator-1α expression levels are downregulated, and acetylated peroxisome proliferator-activated receptor-γ coactivator-1α expression levels are upregulated in patients and dairy cows with non-alcoholic fatty liver disease, as well as in high-fat diet and ob/ob mice. MiR-181a overexpression inhibits the sirtuin1-peroxisome proliferator-activated receptor-γ coactivator-1α pathway, reduces insulin sensitivity, and increases gluconeogenesis and lipid synthesis in dairy cow hepatocytes and HepG2 cells. Conversely, silencing of miR-181a over-activates the sirtuin1-peroxisome proliferator-activated receptor-γ coactivator-1α pathway, increases insulin sensitivity and glycogen content, and decreases gluconeogenesis and lipid synthesis in hepatocytes, even under non-esterified fatty acids treatment conditions. Furthermore, miR-181a overexpression or sirtuin1 knockdown in mice increases lipid accumulation and decreases insulin sensitivity and glycogen content in the liver. Taken together, these findings indicate that increased hepatic miR-181a impairs glucose and lipid homeostasis by silencing sirtuin1 in non-alcoholic fatty liver disease.
到目前为止，转录后基因沉默改变对代谢紊乱发展的贡献仍知之甚少。本研究的目的是评估miR-181a在肝脏葡萄糖和脂质代谢调节中的作用。miR-181a在肝脏中大量表达，我们发现非酒精性脂肪性肝病患者和奶牛以及高脂饮食和ob/ob小鼠的血液和肝脏miR-181a水平显著升高。我们确定沉默调节蛋白1是miR-181a的一个靶点。此外，我们发现非酒精性脂肪性肝病患者和奶牛以及高脂饮食和ob/ob小鼠的肝脏沉默调节蛋白1和过氧化物酶体增殖物激活受体γ共激活因子1α表达水平下调，而乙酰化过氧化物酶体增殖物激活受体γ共激活因子1α表达水平上调。miR-181a过表达抑制沉默调节蛋白1-过氧化物酶体增殖物激活受体γ共激活因子1α途径，降低胰岛素敏感性，并增加奶牛肝细胞和HepG2细胞中的糖异生和脂质合成。相反，miR-181a沉默会过度激活沉默调节蛋白1-过氧化物酶体增殖物激活受体γ共激活因子1α途径，增加胰岛素敏感性和糖原含量，并降低肝细胞中的糖异生和脂质合成，即使在非酯化脂肪酸处理条件下也是如此。此外，小鼠中miR-181a过表达或沉默调节蛋白1敲低会增加肝脏中的脂质积累，并降低胰岛素敏感性和糖原含量。综上所述，这些发现表明，在非酒精性脂肪性肝病中，肝脏miR-181a增加通过沉默沉默调节蛋白1损害葡萄糖和脂质稳态。
