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

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

doi:10.18632/oncotarget.20523

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.

Highlights

Non-alcoholic fatty liver disease (NAFLD) is a major metabolic disorder of animals and humans and affects up to 30% of adults and 10% of children in developed countries [1]
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
Western blotting results showed that insulin receptor (IR), protein kinase B (Akt), and glycogen synthase kinase3β (GSK3β) phosphorylation levels and PPARα protein expression levels were significantly decreased, and sterol regulator element-binding protein-1c (SREBP-1c) protein expression levels were significantly increased in the liver samples from dairy cows with NAFLD compared with those from control cows (Supplementary Figure 1A and 1B)

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) is a major metabolic disorder of animals and humans and affects up to 30% of adults and 10% of children in developed countries [1]. Www.impactjournals.com/oncotarget have moderate fatty liver, indicating that up to 50% of dairy cows are at high risk for diseases and reproductive problems [6]. Previous studies showed that NAFLD is strongly associated with increased levels of serum non-esterified fatty acids (NEFA) [11, 12], which participate in many important cellular processes, such as energy storage, cellular membrane synthesis, and intracellular signaling pathways. Chronic elevations in NEFA levels are capable of disturbing multiple metabolic pathways and inducing insulin resistance, endoplasmic reticular stress, oxidative stress, and mitochondrial dysfunction [13,14,15]

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