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Nicotinamide N-methyltransferase mediates lipofibroblast–myofibroblast transition and apoptosis resistance
Metabolism controls cellular phenotype and fate. In this report, we demonstrate that nicotinamide N-methyltransferase (NNMT), a metabolic enzyme that regulates developmental stem cell transitions and tumor progression, is highly expressed in human idiopathic pulmonary fibrosis (IPF) lungs, and is in...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10413354/ https://www.ncbi.nlm.nih.gov/pubmed/37423298 http://dx.doi.org/10.1016/j.jbc.2023.105027 |
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author | Rehan, Mohammad Deskin, Brian Kurundkar, Ashish R. Yadav, Santosh Matsunaga, Yasuka Manges, Justin Smith, Nia Dsouza, Kevin G. Burow, Matthew E. Thannickal, Victor J. |
author_facet | Rehan, Mohammad Deskin, Brian Kurundkar, Ashish R. Yadav, Santosh Matsunaga, Yasuka Manges, Justin Smith, Nia Dsouza, Kevin G. Burow, Matthew E. Thannickal, Victor J. |
author_sort | Rehan, Mohammad |
collection | PubMed |
description | Metabolism controls cellular phenotype and fate. In this report, we demonstrate that nicotinamide N-methyltransferase (NNMT), a metabolic enzyme that regulates developmental stem cell transitions and tumor progression, is highly expressed in human idiopathic pulmonary fibrosis (IPF) lungs, and is induced by the pro-fibrotic cytokine, transforming growth factor-β1 (TGF-β1) in lung fibroblasts. NNMT silencing reduces the expression of extracellular matrix proteins, both constitutively and in response to TGF-β1. Furthermore, NNMT controls the phenotypic transition from homeostatic, pro-regenerative lipofibroblasts to pro-fibrotic myofibroblasts. This effect of NNMT is mediated, in part, by the downregulation of lipogenic transcription factors, TCF21 and PPARγ, and the induction of a less proliferative but more differentiated myofibroblast phenotype. NNMT confers an apoptosis-resistant phenotype to myofibroblasts that is associated with the downregulation of pro-apoptotic members of the Bcl-2 family, including Bim and PUMA. Together, these studies indicate a critical role for NNMT in the metabolic reprogramming of fibroblasts to a pro-fibrotic and apoptosis-resistant phenotype and support the concept that targeting this enzyme may promote regenerative responses in chronic fibrotic disorders such as IPF. |
format | Online Article Text |
id | pubmed-10413354 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-104133542023-08-11 Nicotinamide N-methyltransferase mediates lipofibroblast–myofibroblast transition and apoptosis resistance Rehan, Mohammad Deskin, Brian Kurundkar, Ashish R. Yadav, Santosh Matsunaga, Yasuka Manges, Justin Smith, Nia Dsouza, Kevin G. Burow, Matthew E. Thannickal, Victor J. J Biol Chem Research Article Metabolism controls cellular phenotype and fate. In this report, we demonstrate that nicotinamide N-methyltransferase (NNMT), a metabolic enzyme that regulates developmental stem cell transitions and tumor progression, is highly expressed in human idiopathic pulmonary fibrosis (IPF) lungs, and is induced by the pro-fibrotic cytokine, transforming growth factor-β1 (TGF-β1) in lung fibroblasts. NNMT silencing reduces the expression of extracellular matrix proteins, both constitutively and in response to TGF-β1. Furthermore, NNMT controls the phenotypic transition from homeostatic, pro-regenerative lipofibroblasts to pro-fibrotic myofibroblasts. This effect of NNMT is mediated, in part, by the downregulation of lipogenic transcription factors, TCF21 and PPARγ, and the induction of a less proliferative but more differentiated myofibroblast phenotype. NNMT confers an apoptosis-resistant phenotype to myofibroblasts that is associated with the downregulation of pro-apoptotic members of the Bcl-2 family, including Bim and PUMA. Together, these studies indicate a critical role for NNMT in the metabolic reprogramming of fibroblasts to a pro-fibrotic and apoptosis-resistant phenotype and support the concept that targeting this enzyme may promote regenerative responses in chronic fibrotic disorders such as IPF. American Society for Biochemistry and Molecular Biology 2023-07-07 /pmc/articles/PMC10413354/ /pubmed/37423298 http://dx.doi.org/10.1016/j.jbc.2023.105027 Text en © 2023 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Research Article Rehan, Mohammad Deskin, Brian Kurundkar, Ashish R. Yadav, Santosh Matsunaga, Yasuka Manges, Justin Smith, Nia Dsouza, Kevin G. Burow, Matthew E. Thannickal, Victor J. Nicotinamide N-methyltransferase mediates lipofibroblast–myofibroblast transition and apoptosis resistance |
title | Nicotinamide N-methyltransferase mediates lipofibroblast–myofibroblast transition and apoptosis resistance |
title_full | Nicotinamide N-methyltransferase mediates lipofibroblast–myofibroblast transition and apoptosis resistance |
title_fullStr | Nicotinamide N-methyltransferase mediates lipofibroblast–myofibroblast transition and apoptosis resistance |
title_full_unstemmed | Nicotinamide N-methyltransferase mediates lipofibroblast–myofibroblast transition and apoptosis resistance |
title_short | Nicotinamide N-methyltransferase mediates lipofibroblast–myofibroblast transition and apoptosis resistance |
title_sort | nicotinamide n-methyltransferase mediates lipofibroblast–myofibroblast transition and apoptosis resistance |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10413354/ https://www.ncbi.nlm.nih.gov/pubmed/37423298 http://dx.doi.org/10.1016/j.jbc.2023.105027 |
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