Oncotarget

Research Papers:

Upregulation of miR-181a impairs hepatic glucose and lipid homeostasis

Xiliang Du, Yuchen Yang, Chuang Xu, Zhicheng Peng, Min Zhang, Lin Lei, Wenwen Gao, Yuhao Dong, Zhen Shi, Xudong Sun, Zhe Wang, Xiaobing Li, Xinwei Li _ and Guowen Liu

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Oncotarget. 2017; 8:91362-91378. https://doi.org/10.18632/oncotarget.20523

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Abstract

Xiliang Du1, Yuchen Yang1, Chuang Xu2, Zhicheng Peng1, Min Zhang1, Lin Lei1, Wenwen Gao1, Yuhao Dong1, Zhen Shi1, Xudong Sun1, Zhe Wang1, Xiaobing Li1, Xinwei Li1 and Guowen Liu1

1Key Laboratory of Zoonosis, Ministry of Education, College of Veterinary Medicine, Jilin University, Changchun 130062, China

2College of Animal Science and Veterinary Medicine, Heilongjiang Bayi Agricultural University, Daqing 163319, China

Correspondene to:

Xinwei Li, email: lixinwei100@126.com

Guowen Liu, email: liuguowen2008@163.com

Keywords: non-alcoholic fatty liver disease, dairy cows, non-esterified fatty acids, miR-181a, sirtuin1

Received: July 03, 2017    Accepted: August 06, 2017    Published: August 24, 2017

ABSTRACT

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.


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