miR-15a-3p Protects Against Isoniazid-Induced Liver Injury via Suppressing N-Acetyltransferase 2 Expression
Isoniazid (INH), an effective first-line drug for tuberculosis treatment, has been reported to be associated with hepatotoxicity for decades, but the underlying mechanisms are poorly understood. N-acetyltransferase 2 (NAT2) is a Phase II enzyme that specifically catalyzes the acetylation of INH, and...
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Frontiers Media S.A.
2021
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oai:doaj.org-article:02d22b49417247feb9466c7a5236654f2021-11-30T12:56:56ZmiR-15a-3p Protects Against Isoniazid-Induced Liver Injury via Suppressing N-Acetyltransferase 2 Expression2296-889X10.3389/fmolb.2021.752072https://doaj.org/article/02d22b49417247feb9466c7a5236654f2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fmolb.2021.752072/fullhttps://doaj.org/toc/2296-889XIsoniazid (INH), an effective first-line drug for tuberculosis treatment, has been reported to be associated with hepatotoxicity for decades, but the underlying mechanisms are poorly understood. N-acetyltransferase 2 (NAT2) is a Phase II enzyme that specifically catalyzes the acetylation of INH, and NAT2 expression/activity play pivotal roles in INH metabolism, drug efficacy, and toxicity. In this study, we systematically investigated the regulatory roles of microRNA (miRNA) in NAT2 expression and INH-induced liver injury via a series of in silico, in vitro, and in vivo analyses. Four mature miRNAs, including hsa-miR-15a-3p, hsa-miR-628-5p, hsa-miR-1262, and hsa-miR-3132, were predicted to target the NAT2 transcript, and a negative correlation was observed between hsa-miR-15a-3p and NAT2 transcripts in liver samples. Further experiments serially revealed that hsa-miR-15a-3p was able to interact with the 3′-untranslated region (UTR) of NAT2 directly, suppressed the endogenous NAT2 expression, and then inhibited INH-induced NAT2 overexpression as well as INH-induced liver injury, both in liver cells and mouse model. In summary, our results identified hsa-miR-15a-3p as a novel epigenetic factor modulating NAT2 expression and as a protective module against INH-induced liver injury, and provided new clues to elucidate the epigenetic regulatory mechanisms concerning drug-induced liver injury (DILI).Xinmei LiHeng ZhangLin XuYuan JinJiao LuoChuanhai LiKunming ZhaoYuxin ZhengDianke YuYanjie ZhaoFrontiers Media S.A.articleisoniaziddrug-induced liver injuryN-acetyltransferase 2hsa-miR-15a-3pregulationBiology (General)QH301-705.5ENFrontiers in Molecular Biosciences, Vol 8 (2021) |
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DOAJ |
| collection |
DOAJ |
| language |
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| topic |
isoniazid drug-induced liver injury N-acetyltransferase 2 hsa-miR-15a-3p regulation Biology (General) QH301-705.5 |
| spellingShingle |
isoniazid drug-induced liver injury N-acetyltransferase 2 hsa-miR-15a-3p regulation Biology (General) QH301-705.5 Xinmei Li Heng Zhang Lin Xu Yuan Jin Jiao Luo Chuanhai Li Kunming Zhao Yuxin Zheng Dianke Yu Yanjie Zhao miR-15a-3p Protects Against Isoniazid-Induced Liver Injury via Suppressing N-Acetyltransferase 2 Expression |
| description |
Isoniazid (INH), an effective first-line drug for tuberculosis treatment, has been reported to be associated with hepatotoxicity for decades, but the underlying mechanisms are poorly understood. N-acetyltransferase 2 (NAT2) is a Phase II enzyme that specifically catalyzes the acetylation of INH, and NAT2 expression/activity play pivotal roles in INH metabolism, drug efficacy, and toxicity. In this study, we systematically investigated the regulatory roles of microRNA (miRNA) in NAT2 expression and INH-induced liver injury via a series of in silico, in vitro, and in vivo analyses. Four mature miRNAs, including hsa-miR-15a-3p, hsa-miR-628-5p, hsa-miR-1262, and hsa-miR-3132, were predicted to target the NAT2 transcript, and a negative correlation was observed between hsa-miR-15a-3p and NAT2 transcripts in liver samples. Further experiments serially revealed that hsa-miR-15a-3p was able to interact with the 3′-untranslated region (UTR) of NAT2 directly, suppressed the endogenous NAT2 expression, and then inhibited INH-induced NAT2 overexpression as well as INH-induced liver injury, both in liver cells and mouse model. In summary, our results identified hsa-miR-15a-3p as a novel epigenetic factor modulating NAT2 expression and as a protective module against INH-induced liver injury, and provided new clues to elucidate the epigenetic regulatory mechanisms concerning drug-induced liver injury (DILI). |
| format |
article |
| author |
Xinmei Li Heng Zhang Lin Xu Yuan Jin Jiao Luo Chuanhai Li Kunming Zhao Yuxin Zheng Dianke Yu Yanjie Zhao |
| author_facet |
Xinmei Li Heng Zhang Lin Xu Yuan Jin Jiao Luo Chuanhai Li Kunming Zhao Yuxin Zheng Dianke Yu Yanjie Zhao |
| author_sort |
Xinmei Li |
| title |
miR-15a-3p Protects Against Isoniazid-Induced Liver Injury via Suppressing N-Acetyltransferase 2 Expression |
| title_short |
miR-15a-3p Protects Against Isoniazid-Induced Liver Injury via Suppressing N-Acetyltransferase 2 Expression |
| title_full |
miR-15a-3p Protects Against Isoniazid-Induced Liver Injury via Suppressing N-Acetyltransferase 2 Expression |
| title_fullStr |
miR-15a-3p Protects Against Isoniazid-Induced Liver Injury via Suppressing N-Acetyltransferase 2 Expression |
| title_full_unstemmed |
miR-15a-3p Protects Against Isoniazid-Induced Liver Injury via Suppressing N-Acetyltransferase 2 Expression |
| title_sort |
mir-15a-3p protects against isoniazid-induced liver injury via suppressing n-acetyltransferase 2 expression |
| publisher |
Frontiers Media S.A. |
| publishDate |
2021 |
| url |
https://doaj.org/article/02d22b49417247feb9466c7a5236654f |
| work_keys_str_mv |
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