Comprehensive analysis of LncRNAs expression profiles in an in vitro model of steatosis treated with Exendin-4

Khaoula Errafii,Neyla S Al-Akl,Abdelilah Arredouani,Olfa Khalifa

doi:10.1186/s12967-021-02885-4

Khaoula Errafii, Neyla S Al-Akl + Show 2 more

Open Access

https://doi.org/10.1186/s12967-021-02885-4

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Abstract

Background and aimsThe hallmark of non-alcoholic fatty liver disease (NAFLD) is the excessive hepatic lipid accumulation. Currently, no pharmacotherapy exists for NAFLD. However, the glucagon-like peptide-1 receptor agonists have recently emerged as potential therapeutics. Here, we sought to identify the long non-coding RNAs (LncRNAs) associated with the steatosis improvement induced by the GLP-1R agonist Exendin-4 (Ex-4) in vitro.MethodsSteatosis was induced in HepG2 cells with oleic acid. The transcriptomic profiling was performed using total RNA extracted from untreated, steatotic, and Ex-4-treated steatotic cells. We validated a subset of differentially expressed LncRNAs with qRT-PCR and identified the most significantly enriched cellular functions associated with the relevant LncRNAs.ResultsWe confirm that Ex-4 improves steatosis in HepG2 cells. We found 379 and 180 differentially expressed LncRNAs between untreated and steatotic cells and between steatotic and Ex-4-treated steatotic cells, respectively. Interestingly, 22 upregulated LncRNAs in steatotic cells became downregulated with Ex-4 exposure, while 50 downregulated LncRNAs in steatotic cells became upregulated in the presence of Ex-4. Although some LncRNAs, such as MALAT1, H19, and NEAT1, were previously associated with NAFLD, the association of others with steatosis and the positive effect of Ex-4 is being reported for the first time. Functional enrichment analysis identified many critical pathways, including fatty acid and pyruvate metabolism, and insulin, PPAR, Wnt, TGF-β, mTOR, VEGF, NOD-like, and Toll-like receptors signaling pathways.ConclusionOur results suggest that LncRNAs may play essential roles in the mechanisms underlying steatosis improvement in response to GLP-1R agonists and warrant further functional studies.

Highlights

Non-alcoholic Fatty Liver Diseases or (NAFLD) is a broad term that covers the whole spectrum of fatty liver disease, including steatosis, steatohepatitis, fibrosis, and cirrhosis [1]
22 upregulated long non-coding RNAs (LncRNAs) in steatotic cells became downregulated with Ex-4 exposure, while 50 down‐ regulated LncRNAs in steatotic cells became upregulated in the presence of Ex-4
Some LncRNAs, such as MALAT1, H19, and NEAT1, were previously associated with non-alcoholic fatty liver disease (NAFLD), the association of others with steatosis and the positive effect of Ex-4 is being reported for the first time

Summary

Introduction

Non-alcoholic Fatty Liver Diseases or (NAFLD) is a broad term that covers the whole spectrum of fatty liver disease, including steatosis, steatohepatitis, fibrosis, and cirrhosis [1]. In the recent few years, Glucagon-like peptide-1 receptor agonists (GLP-1RAs), already approved for the treatment of type 2 diabetes (T2D) [7], have emerged as potential drugs for the treatment of NAFLD due to their appetite and food intake reducing effects [8], and their ability to increase lipid oxidation [9]. Recent in vivo and in vitro studies have tested the impact of the GLP-1RAs on liver fat content and have shown promising results [8]. These agents were suggested as potential options for managing and slowing NAFLD progression [15]. We sought to identify the long non-coding RNAs (LncRNAs) associated with the steatosis improvement induced by the GLP-1R agonist Exendin-4 (Ex-4) in vitro

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