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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MDPI AG
2021-07-01
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| Online Access: | https://www.mdpi.com/2073-4409/10/8/1883 |
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| author | Biljana Atanasovska Sander S. Rensen Glenn Marsman Ronit Shiri-Sverdlov Sebo Withoff Folkert Kuipers Cisca Wijmenga Bart van de Sluis Jingyuan Fu |
| author_facet | Biljana Atanasovska Sander S. Rensen Glenn Marsman Ronit Shiri-Sverdlov Sebo Withoff Folkert Kuipers Cisca Wijmenga Bart van de Sluis Jingyuan Fu |
| author_sort | Biljana Atanasovska |
| collection | DOAJ |
| 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 <i>A20</i> and <i>NFKBIA</i>. The lncTNF we identified in the NF-κB signaling pathway may represent a novel target for controlling liver inflammation. |
| first_indexed | 2024-03-10T08:55:27Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T08:55:27Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-4f5d61b440834d03a066e3754370c9602023-11-22T07:08:40ZengMDPI AGCells2073-44092021-07-01108188310.3390/cells10081883Long Non-Coding RNAs Involved in Progression of Non-Alcoholic Fatty Liver Disease to SteatohepatitisBiljana Atanasovska0Sander S. Rensen1Glenn Marsman2Ronit Shiri-Sverdlov3Sebo Withoff4Folkert Kuipers5Cisca Wijmenga6Bart van de Sluis7Jingyuan Fu8Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Surgery, Maastricht University and NUTRIM School for Nutrition and Translational Research in Metabolism, 6229 HX Maastricht, The NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartments of Molecular Genetics, Molecular Cell Biology & Population Genetics, Nutrition & Toxicology Research (NUTRIM) Institutes of Maastricht, University of Maastricht, 6229 HX Maastricht, The NetherlandsDepartment of Genetics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Genetics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsDepartment of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The NetherlandsNon-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 <i>A20</i> and <i>NFKBIA</i>. The lncTNF we identified in the NF-κB signaling pathway may represent a novel target for controlling liver inflammation.https://www.mdpi.com/2073-4409/10/8/1883non-alcoholic fatty liver diseasefunctional genomicslong non-coding RNAs |
| spellingShingle | Biljana Atanasovska Sander S. Rensen Glenn Marsman Ronit Shiri-Sverdlov Sebo Withoff Folkert Kuipers Cisca Wijmenga Bart van de Sluis Jingyuan Fu Long Non-Coding RNAs Involved in Progression of Non-Alcoholic Fatty Liver Disease to Steatohepatitis Cells non-alcoholic fatty liver disease functional genomics long non-coding RNAs |
| 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 | non-alcoholic fatty liver disease functional genomics long non-coding RNAs |
| url | https://www.mdpi.com/2073-4409/10/8/1883 |
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