Upregulation of microRNA-125b-5p alleviates acute liver failure by regulating the Keap1/Nrf2/HO-1 pathway
BackgroundAcute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are the two most common subtypes of liver failure. They are both life-threatening clinical problems with high short-term mortality. Although liver transplantation is an effective therapeutic, its application is limited due...
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.988668/full |
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| author | Ya-Chao Tao Ya-Chao Tao Yong-Hong Wang Yong-Hong Wang Meng-Lan Wang Meng-Lan Wang Wei Jiang Wei Jiang Dong-Bo Wu Dong-Bo Wu En-Qiang Chen En-Qiang Chen Hong Tang Hong Tang |
| author_facet | Ya-Chao Tao Ya-Chao Tao Yong-Hong Wang Yong-Hong Wang Meng-Lan Wang Meng-Lan Wang Wei Jiang Wei Jiang Dong-Bo Wu Dong-Bo Wu En-Qiang Chen En-Qiang Chen Hong Tang Hong Tang |
| author_sort | Ya-Chao Tao |
| collection | DOAJ |
| description | BackgroundAcute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are the two most common subtypes of liver failure. They are both life-threatening clinical problems with high short-term mortality. Although liver transplantation is an effective therapeutic, its application is limited due to the shortage of donor organs. Given that both ACLF and ALF are driven by excessive inflammation in the initial stage, molecules targeting inflammation may benefit the two conditions. MicroRNAs (miRNAs) are a group of small endogenous noncoding interfering RNA molecules. Regulation of miRNAs related to inflammation may serve as promising interventions for the treatment of liver failure.AimsTo explore the role and mechanism of miR-125b-5p in the development of liver failure.MethodsSix human liver tissues were categorized into HBV-non-ACLF and HBV-ACLF groups. Differentially expressed miRNAs (DE-miRNAs) were screened and identified through high-throughput sequencing analysis. Among these DE-miRNAs, miR-125b-5p was selected for further study of its role and mechanism in lipopolysaccharide (LPS)/D-galactosamine (D-GalN) -challenged Huh7 cells and mice in vitro and in vivo.ResultsA total of 75 DE-miRNAs were obtained. Of these DE-miRNAs, miR-125b-5p was the focus of further investigation based on our previous findings and preliminary results. We preliminarily observed that the levels of miR-125b-5p were lower in the HBV-ACLF group than in the HBV-non-ACLF group. Meanwhile, LPS/D-GalN-challenged mice and Huh7 cells both showed decreased miR-125b-5p levels when compared to their untreated control group, suggesting that miR-125b-5p may have a protective role against liver injury, regardless of ACLF or ALF. Subsequent results revealed that miR-125b-5p not only inhibited Huh7 cell apoptosis in vitro but also relieved mouse ALF in vivo with evidence of improved liver histology, decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and reduced tumor necrosis factor-α (TNF-α) and IL-1β levels. Based on the results of a biological prediction website, microRNA.org, Kelch-like ECH-associated protein 1 (Keap1) was predicted to be one of the target genes of miR-125b-5p, which was verified by a dual-luciferase reporter gene assay. Western blot results in vitro and in vivo showed that miR-125b-5p could decrease the expression of Keap1 and cleaved caspase-3 while upregulating the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1(HO-1).ConclusionUpregulation of miR-125b-5p can alleviate acute liver failure by regulating the Keap1/Nrf2/HO-1 pathway, and regulation of miR-125b-5p may serve as an alternative intervention for liver failure. |
| first_indexed | 2024-04-12T10:17:45Z |
| format | Article |
| id | doaj.art-33851b400623424685077438bbed9a9a |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T10:17:45Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-33851b400623424685077438bbed9a9a2022-12-22T03:37:10ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-10-011310.3389/fimmu.2022.988668988668Upregulation of microRNA-125b-5p alleviates acute liver failure by regulating the Keap1/Nrf2/HO-1 pathwayYa-Chao Tao0Ya-Chao Tao1Yong-Hong Wang2Yong-Hong Wang3Meng-Lan Wang4Meng-Lan Wang5Wei Jiang6Wei Jiang7Dong-Bo Wu8Dong-Bo Wu9En-Qiang Chen10En-Qiang Chen11Hong Tang12Hong Tang13Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, ChinaDivision of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, ChinaCenter of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, ChinaDivision of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, ChinaCenter of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, ChinaDivision of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, ChinaCenter of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, ChinaDivision of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, ChinaCenter of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, ChinaDivision of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, ChinaCenter of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, ChinaDivision of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, ChinaCenter of Infectious Diseases, West China Hospital, Sichuan University, Chengdu, ChinaDivision of Infectious Diseases, State Key Laboratory of Biotherapy, Sichuan University, Chengdu, ChinaBackgroundAcute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are the two most common subtypes of liver failure. They are both life-threatening clinical problems with high short-term mortality. Although liver transplantation is an effective therapeutic, its application is limited due to the shortage of donor organs. Given that both ACLF and ALF are driven by excessive inflammation in the initial stage, molecules targeting inflammation may benefit the two conditions. MicroRNAs (miRNAs) are a group of small endogenous noncoding interfering RNA molecules. Regulation of miRNAs related to inflammation may serve as promising interventions for the treatment of liver failure.AimsTo explore the role and mechanism of miR-125b-5p in the development of liver failure.MethodsSix human liver tissues were categorized into HBV-non-ACLF and HBV-ACLF groups. Differentially expressed miRNAs (DE-miRNAs) were screened and identified through high-throughput sequencing analysis. Among these DE-miRNAs, miR-125b-5p was selected for further study of its role and mechanism in lipopolysaccharide (LPS)/D-galactosamine (D-GalN) -challenged Huh7 cells and mice in vitro and in vivo.ResultsA total of 75 DE-miRNAs were obtained. Of these DE-miRNAs, miR-125b-5p was the focus of further investigation based on our previous findings and preliminary results. We preliminarily observed that the levels of miR-125b-5p were lower in the HBV-ACLF group than in the HBV-non-ACLF group. Meanwhile, LPS/D-GalN-challenged mice and Huh7 cells both showed decreased miR-125b-5p levels when compared to their untreated control group, suggesting that miR-125b-5p may have a protective role against liver injury, regardless of ACLF or ALF. Subsequent results revealed that miR-125b-5p not only inhibited Huh7 cell apoptosis in vitro but also relieved mouse ALF in vivo with evidence of improved liver histology, decreased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and reduced tumor necrosis factor-α (TNF-α) and IL-1β levels. Based on the results of a biological prediction website, microRNA.org, Kelch-like ECH-associated protein 1 (Keap1) was predicted to be one of the target genes of miR-125b-5p, which was verified by a dual-luciferase reporter gene assay. Western blot results in vitro and in vivo showed that miR-125b-5p could decrease the expression of Keap1 and cleaved caspase-3 while upregulating the expression of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase-1(HO-1).ConclusionUpregulation of miR-125b-5p can alleviate acute liver failure by regulating the Keap1/Nrf2/HO-1 pathway, and regulation of miR-125b-5p may serve as an alternative intervention for liver failure.https://www.frontiersin.org/articles/10.3389/fimmu.2022.988668/fullacute liver failureacute-on-chronic liver failuremicroRNA-125b-5pKelch-like ECH-associated protein 1high-throughput sequencinginflammation |
| spellingShingle | Ya-Chao Tao Ya-Chao Tao Yong-Hong Wang Yong-Hong Wang Meng-Lan Wang Meng-Lan Wang Wei Jiang Wei Jiang Dong-Bo Wu Dong-Bo Wu En-Qiang Chen En-Qiang Chen Hong Tang Hong Tang Upregulation of microRNA-125b-5p alleviates acute liver failure by regulating the Keap1/Nrf2/HO-1 pathway Frontiers in Immunology acute liver failure acute-on-chronic liver failure microRNA-125b-5p Kelch-like ECH-associated protein 1 high-throughput sequencing inflammation |
| title | Upregulation of microRNA-125b-5p alleviates acute liver failure by regulating the Keap1/Nrf2/HO-1 pathway |
| title_full | Upregulation of microRNA-125b-5p alleviates acute liver failure by regulating the Keap1/Nrf2/HO-1 pathway |
| title_fullStr | Upregulation of microRNA-125b-5p alleviates acute liver failure by regulating the Keap1/Nrf2/HO-1 pathway |
| title_full_unstemmed | Upregulation of microRNA-125b-5p alleviates acute liver failure by regulating the Keap1/Nrf2/HO-1 pathway |
| title_short | Upregulation of microRNA-125b-5p alleviates acute liver failure by regulating the Keap1/Nrf2/HO-1 pathway |
| title_sort | upregulation of microrna 125b 5p alleviates acute liver failure by regulating the keap1 nrf2 ho 1 pathway |
| topic | acute liver failure acute-on-chronic liver failure microRNA-125b-5p Kelch-like ECH-associated protein 1 high-throughput sequencing inflammation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.988668/full |
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