LncRNA-AK012226 Is Involved in Fat Accumulation in db/db Mice Fatty Liver and Non-alcoholic Fatty Liver Disease Cell Model

Xingtian Chen,Dan Zhao,Ganxiang Yu,Jie He,Hui Yang,Yun Zhong,Yuqiang Nie,Ting Chen,Shiming Liu,Chengxin Gu,Ken Chen,Yangzhi Xu

doi:10.3389/fphar.2018.00888

Abstract

Instances of obesity and related metabolic abnormalities are increasing across the world. Non-alcoholic fatty liver disease (NAFLD) is a common disorder in obese people and is becoming the leading cause of hepatocellular carcinoma. Recently, long non-coding RNAs (lncRNAs) have been proven to play remarkable roles in numerous biological processes and human diseases, including NAFLD. However, the function of lncRNA in NAFLD pathogenesis remains largely unknown. The aim of this study was to explore the lncRNA expression profile in NAFLD mice and to identify novel lncRNAs involved in the pathogenesis of NAFLD. We performed microarray analysis to compare the expression profiles of lncRNAs and mRNAs in the liver of diabetic db/db mice with NAFLD and normal mice. A total of 3360 lncRNAs (2048 up-regulated and 1312 down-regulated) and 2685 mRNAs (1195 up-regulated and 1490 down-regulated) were found to be differentially expressed between the NAFLD and control groups. Real-time PCR validation of five differentially expressed lncRNAs in the liver samples was consistent with the microarray results. Besides, the up-regulated lncRNA, AK012226, was also significantly increased in an NCTC1469 NAFLD cellular model. Thus, the up-regulated lncRNA, AK012226, was chosen for subsequent studies. A co-expression network of AK012226-mRNAs was constructed and bioinformatic analysis of these co-expressed mRNAs indicated that they were enriched in the PPAR signaling pathway. Furthermore, Nile red staining and flow cytometry analysis revealed that knockdown of AK012226 by siRNA significantly reduced the lipid accumulation in the NCTC1469 cells treated with free fatty acids. In conclusion, the present study identifies the dysregulated lncRNAs and mRNAs involved in NAFLD, and in particular, a novel lncRNA, AK012226, was identified to be associated with lipid accumulation in NAFLD.

Highlights

Instances of obesity and related metabolic syndrome are increasing around the world
Using several approaches for validation and mechanistic elucidation, we demonstrate that an long non-coding RNAs (lncRNAs), AK012226, plays a crucial role in lipid accumulation and, thereby, in the pathogenesis of non-alcoholic fatty liver disease (NAFLD)
It was found that a total of 3360 lncRNAs (2048 upregulated and 1312 downregulated) and 2685 mRNAs (1195 upregulated and 1490 downregulated) were differentially expressed between the NAFLD and control groups

Summary

Introduction

Instances of obesity and related metabolic syndrome are increasing around the world. According to the Global Health Observatory (GHO) data from World Health Organization (WHO), an estimated 600 million adults, accounting for approximately 13% of the world’s adult, were obese in 2014; this number has more than doubled since 1980 (WHO, 2014). Role of lncRNAs in NAFLD association with obesity, non-alcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease, worldwide. It is estimated that its prevalence is 20–30% in the general population and 70% in patients with type 2 diabetes and is strikingly increased to 90–95% in obese people (Non-alcoholic Fatty Liver Disease Study Group et al, 2015; Portillo-Sanchez et al, 2015; Younossi et al, 2016). NAFLD is regarded as the hepatic manifestation of metabolic syndrome. NAFLD is a risk factor for hepatocellular carcinoma (HCC), accounting for up to 25% of the cases of HCC in the western countries, and has become one of the most important public health problems (Michelotti et al, 2013)

Objectives

Methods

Results

Discussion

Conclusion