LncRNA SRA promotes hepatic steatosis through repressing the expression of adipose triglyceride lipase (ATGL).

Gang Chen,Dongsheng Yu,Xue Nian,Ronald J Koenig,Liang Sheng,Bin Xu,Junyi Liu

doi:10.1038/srep35531

Abstract

Nonalcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease, manifests as an over-accumulation of hepatic fat. We have recently shown that mice with genetic knockout of a long non-coding RNA (lncRNA) steroid receptor RNA activator (SRA) (SRAKO) are resistant to high fat diet-induced obesity with a phenotype that includes improved glucose tolerance and attenuated hepatic steatosis. The underlying mechanism was investigated in the present study. We found that hepatic levels of SRA and adipose triglyceride lipase (ATGL), a major hepatic triacylglycerol (TAG) hydrolase, were inversely regulated by fasting in mice, and the expression of liver ATGL was induced by SRAKO under normal and high fat diet (HFD) feeding. Loss of SRA in primary hepatocytes or a hepatocyte cell line upregulates, but forced expression of SRA inhibits ATGL expression and free fatty acids (FFA) β-oxidation. SRA inhibits ATGL promoter activity, primarily by inhibiting the otherwise-inductive effects of the transcription factor, forkhead box protein O1 (FoxO1). Our data reveal a novel function of SRA in promoting hepatic steatosis through repression of ATGL expression.

Highlights

Steroid receptor RNA activator (SRA) was initially characterized as a lncRNA that functions as an RNA coactivator to enhance steroid nuclear receptor-dependent gene expression[15]
To identify key regulator(s) that may lower hepatic TAG content, we examined the expression of hepatic genes that regulate free fatty acids (FFA) β-oxidation, lipogenesis and very low density lipoprotein (VLDL) secretion in SRAKO mice fed with normal chow
We found that the mRNA levels of Srebp1c, Acly and Fasn were unchanged in cultured primary hepatocytes of SRAKO mice and were uninfluenced by overexpression of SRA or SRAP in the mouse hepatocyte cell line, Hepa[1,2,3,4,5,6] (Supplementary Figure S1), suggesting that the changes in Srebp1c, Acly and Fasn expression seen in Fig. 1a are likely secondary effects of the in vivo situation

Summary

Introduction

Steroid receptor RNA activator (SRA) was initially characterized as a lncRNA that functions as an RNA coactivator to enhance steroid nuclear receptor-dependent gene expression[15]. In addition to reduced fat mass, SRAKO mice have decreased hepatic TAG levels and resistance to diet-induced obesity. These data, for the first time, indicate a role for SRA in hepatic lipid metabolism[29]. We elucidate the mechanism by showing that SRA inhibits the transcriptional activity of forkhead box protein O1 (FoxO1) via an insulin-independent pathway in hepatocytes, reducing the expression of its downstream gene ATGL, which is a key lipolytic enzyme, and subsequently decreasing hepatocyte FFA β-oxidation

Methods

Results

Conclusion