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Metabolic and molecular insights into an essential role of nicotinamide phosphoribosyltransferase

Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein implicated in the pathogenesis of acute respiratory distress syndrome, aging, cancer, coronary heart diseases, diabetes, nonalcoholic fatty liver disease, obesity, rheumatoid arthritis, and sepsis. However, the underlying molecu...

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Autores principales: Zhang, Li Q, Van Haandel, Leon, Xiong, Min, Huang, Peixin, Heruth, Daniel P, Bi, Charlie, Gaedigk, Roger, Jiang, Xun, Li, Ding-You, Wyckoff, Gerald, Grigoryev, Dmitry N, Gao, Li, Li, Linheng, Wu, Min, Leeder, J Steven, Ye, Shui Qing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386535/
https://www.ncbi.nlm.nih.gov/pubmed/28333140
http://dx.doi.org/10.1038/cddis.2017.132
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author Zhang, Li Q
Van Haandel, Leon
Xiong, Min
Huang, Peixin
Heruth, Daniel P
Bi, Charlie
Gaedigk, Roger
Jiang, Xun
Li, Ding-You
Wyckoff, Gerald
Grigoryev, Dmitry N
Gao, Li
Li, Linheng
Wu, Min
Leeder, J Steven
Ye, Shui Qing
author_facet Zhang, Li Q
Van Haandel, Leon
Xiong, Min
Huang, Peixin
Heruth, Daniel P
Bi, Charlie
Gaedigk, Roger
Jiang, Xun
Li, Ding-You
Wyckoff, Gerald
Grigoryev, Dmitry N
Gao, Li
Li, Linheng
Wu, Min
Leeder, J Steven
Ye, Shui Qing
author_sort Zhang, Li Q
collection PubMed
description Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein implicated in the pathogenesis of acute respiratory distress syndrome, aging, cancer, coronary heart diseases, diabetes, nonalcoholic fatty liver disease, obesity, rheumatoid arthritis, and sepsis. However, the underlying molecular mechanisms of NAMPT in these physiological and pathological processes are not fully understood. Here, we provide experimental evidence that a Nampt gene homozygous knockout (Nampt(−/−)) resulted in lethality at an early stage of mouse embryonic development and death within 5–10 days in adult mice accompanied by a 25.24±2.22% body weight loss, after the tamoxifen induction of Nampt(F/F) × Cre mice. These results substantiate that Nampt is an essential gene for life. In Nampt(−/−) mice versus Nampt(+/+) mice, biochemical assays indicated that liver and intestinal tissue NAD levels were decreased significantly; histological examination showed that mouse intestinal villi were atrophic and disrupted, and visceral fat was depleted; mass spectrometry detected unusual higher serum polyunsaturated fatty acid containing triglycerides. RNA-seq analyses of both mouse and human pediatric liver transcriptomes have convergently revealed that NAMPT is involved in key basic cellular functions such as transcription, translation, cell signaling, and fundamental metabolism. Notably, the expression of all eight enzymes in the tricarboxylic acid cycle were decreased significantly in the Nampt(−/−) mice. These findings prompt us to posit that adult Nampt(−/−) mouse lethality is a result of a short supply of ATP from compromised intestinal absorption of nutrients from digested food, which leads to the exhaustion of body fat stores.
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spelling pubmed-53865352017-04-27 Metabolic and molecular insights into an essential role of nicotinamide phosphoribosyltransferase Zhang, Li Q Van Haandel, Leon Xiong, Min Huang, Peixin Heruth, Daniel P Bi, Charlie Gaedigk, Roger Jiang, Xun Li, Ding-You Wyckoff, Gerald Grigoryev, Dmitry N Gao, Li Li, Linheng Wu, Min Leeder, J Steven Ye, Shui Qing Cell Death Dis Original Article Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein implicated in the pathogenesis of acute respiratory distress syndrome, aging, cancer, coronary heart diseases, diabetes, nonalcoholic fatty liver disease, obesity, rheumatoid arthritis, and sepsis. However, the underlying molecular mechanisms of NAMPT in these physiological and pathological processes are not fully understood. Here, we provide experimental evidence that a Nampt gene homozygous knockout (Nampt(−/−)) resulted in lethality at an early stage of mouse embryonic development and death within 5–10 days in adult mice accompanied by a 25.24±2.22% body weight loss, after the tamoxifen induction of Nampt(F/F) × Cre mice. These results substantiate that Nampt is an essential gene for life. In Nampt(−/−) mice versus Nampt(+/+) mice, biochemical assays indicated that liver and intestinal tissue NAD levels were decreased significantly; histological examination showed that mouse intestinal villi were atrophic and disrupted, and visceral fat was depleted; mass spectrometry detected unusual higher serum polyunsaturated fatty acid containing triglycerides. RNA-seq analyses of both mouse and human pediatric liver transcriptomes have convergently revealed that NAMPT is involved in key basic cellular functions such as transcription, translation, cell signaling, and fundamental metabolism. Notably, the expression of all eight enzymes in the tricarboxylic acid cycle were decreased significantly in the Nampt(−/−) mice. These findings prompt us to posit that adult Nampt(−/−) mouse lethality is a result of a short supply of ATP from compromised intestinal absorption of nutrients from digested food, which leads to the exhaustion of body fat stores. Nature Publishing Group 2017-03 2017-03-23 /pmc/articles/PMC5386535/ /pubmed/28333140 http://dx.doi.org/10.1038/cddis.2017.132 Text en Copyright © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
spellingShingle Original Article
Zhang, Li Q
Van Haandel, Leon
Xiong, Min
Huang, Peixin
Heruth, Daniel P
Bi, Charlie
Gaedigk, Roger
Jiang, Xun
Li, Ding-You
Wyckoff, Gerald
Grigoryev, Dmitry N
Gao, Li
Li, Linheng
Wu, Min
Leeder, J Steven
Ye, Shui Qing
Metabolic and molecular insights into an essential role of nicotinamide phosphoribosyltransferase
title Metabolic and molecular insights into an essential role of nicotinamide phosphoribosyltransferase
title_full Metabolic and molecular insights into an essential role of nicotinamide phosphoribosyltransferase
title_fullStr Metabolic and molecular insights into an essential role of nicotinamide phosphoribosyltransferase
title_full_unstemmed Metabolic and molecular insights into an essential role of nicotinamide phosphoribosyltransferase
title_short Metabolic and molecular insights into an essential role of nicotinamide phosphoribosyltransferase
title_sort metabolic and molecular insights into an essential role of nicotinamide phosphoribosyltransferase
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386535/
https://www.ncbi.nlm.nih.gov/pubmed/28333140
http://dx.doi.org/10.1038/cddis.2017.132
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