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Long Non-Coding RNAs Involved in Progression of Non-Alcoholic Fatty Liver Disease to Steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and is characterized by different stages varying from benign fat accumulation to non-alcoholic steatohepatitis (NASH) that may progress to cirrhosis and liver cancer. In recent years, a regulatory role of long non-...

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Autores principales: Atanasovska, Biljana, Rensen, Sander S., Marsman, Glenn, Shiri-Sverdlov, Ronit, Withoff, Sebo, Kuipers, Folkert, Wijmenga, Cisca, van de Sluis, Bart, Fu, Jingyuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394311/
https://www.ncbi.nlm.nih.gov/pubmed/34440652
http://dx.doi.org/10.3390/cells10081883
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author Atanasovska, Biljana
Rensen, Sander S.
Marsman, Glenn
Shiri-Sverdlov, Ronit
Withoff, Sebo
Kuipers, Folkert
Wijmenga, Cisca
van de Sluis, Bart
Fu, Jingyuan
author_facet Atanasovska, Biljana
Rensen, Sander S.
Marsman, Glenn
Shiri-Sverdlov, Ronit
Withoff, Sebo
Kuipers, Folkert
Wijmenga, Cisca
van de Sluis, Bart
Fu, Jingyuan
author_sort Atanasovska, Biljana
collection PubMed
description Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and is characterized by different stages varying from benign fat accumulation to non-alcoholic steatohepatitis (NASH) that may progress to cirrhosis and liver cancer. In recent years, a regulatory role of long non-coding RNAs (lncRNAs) in NAFLD has emerged. Therefore, we aimed to characterize the still poorly understood lncRNA contribution to disease progression. Transcriptome analysis in 60 human liver samples with various degrees of NAFLD/NASH was combined with a functional genomics experiment in an in vitro model where we exposed HepG2 cells to free fatty acids (FFA) to induce steatosis, then stimulated them with tumor necrosis factor alpha (TNFα) to mimic inflammation. Bioinformatics analyses provided a functional prediction of novel lncRNAs. We further functionally characterized the involvement of one novel lncRNA in the nuclear-factor-kappa B (NF-κB) signaling pathway by its silencing in Hepatoma G2 (HepG2) cells. We identified 730 protein-coding genes and 18 lncRNAs that responded to FFA/TNFα and associated with human NASH phenotypes with consistent effect direction, with most being linked to inflammation. One novel intergenic lncRNA, designated lncTNF, was 20-fold up-regulated upon TNFα stimulation in HepG2 cells and positively correlated with lobular inflammation in human liver samples. Silencing lncTNF in HepG2 cells reduced NF-κB activity and suppressed expression of the NF-κB target genes A20 and NFKBIA. The lncTNF we identified in the NF-κB signaling pathway may represent a novel target for controlling liver inflammation.
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spelling pubmed-83943112021-08-28 Long Non-Coding RNAs Involved in Progression of Non-Alcoholic Fatty Liver Disease to Steatohepatitis Atanasovska, Biljana Rensen, Sander S. Marsman, Glenn Shiri-Sverdlov, Ronit Withoff, Sebo Kuipers, Folkert Wijmenga, Cisca van de Sluis, Bart Fu, Jingyuan Cells Article Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease and is characterized by different stages varying from benign fat accumulation to non-alcoholic steatohepatitis (NASH) that may progress to cirrhosis and liver cancer. In recent years, a regulatory role of long non-coding RNAs (lncRNAs) in NAFLD has emerged. Therefore, we aimed to characterize the still poorly understood lncRNA contribution to disease progression. Transcriptome analysis in 60 human liver samples with various degrees of NAFLD/NASH was combined with a functional genomics experiment in an in vitro model where we exposed HepG2 cells to free fatty acids (FFA) to induce steatosis, then stimulated them with tumor necrosis factor alpha (TNFα) to mimic inflammation. Bioinformatics analyses provided a functional prediction of novel lncRNAs. We further functionally characterized the involvement of one novel lncRNA in the nuclear-factor-kappa B (NF-κB) signaling pathway by its silencing in Hepatoma G2 (HepG2) cells. We identified 730 protein-coding genes and 18 lncRNAs that responded to FFA/TNFα and associated with human NASH phenotypes with consistent effect direction, with most being linked to inflammation. One novel intergenic lncRNA, designated lncTNF, was 20-fold up-regulated upon TNFα stimulation in HepG2 cells and positively correlated with lobular inflammation in human liver samples. Silencing lncTNF in HepG2 cells reduced NF-κB activity and suppressed expression of the NF-κB target genes A20 and NFKBIA. The lncTNF we identified in the NF-κB signaling pathway may represent a novel target for controlling liver inflammation. MDPI 2021-07-25 /pmc/articles/PMC8394311/ /pubmed/34440652 http://dx.doi.org/10.3390/cells10081883 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Atanasovska, Biljana
Rensen, Sander S.
Marsman, Glenn
Shiri-Sverdlov, Ronit
Withoff, Sebo
Kuipers, Folkert
Wijmenga, Cisca
van de Sluis, Bart
Fu, Jingyuan
Long Non-Coding RNAs Involved in Progression of Non-Alcoholic Fatty Liver Disease to Steatohepatitis
title Long Non-Coding RNAs Involved in Progression of Non-Alcoholic Fatty Liver Disease to Steatohepatitis
title_full Long Non-Coding RNAs Involved in Progression of Non-Alcoholic Fatty Liver Disease to Steatohepatitis
title_fullStr Long Non-Coding RNAs Involved in Progression of Non-Alcoholic Fatty Liver Disease to Steatohepatitis
title_full_unstemmed Long Non-Coding RNAs Involved in Progression of Non-Alcoholic Fatty Liver Disease to Steatohepatitis
title_short Long Non-Coding RNAs Involved in Progression of Non-Alcoholic Fatty Liver Disease to Steatohepatitis
title_sort long non-coding rnas involved in progression of non-alcoholic fatty liver disease to steatohepatitis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8394311/
https://www.ncbi.nlm.nih.gov/pubmed/34440652
http://dx.doi.org/10.3390/cells10081883
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