TY - JOUR
T1 - Metabolic and molecular insights into an essential role of nicotinamide phosphoribosyltransferase
AU - Zhang, Li Q.
AU - Haandel, Leon Van
AU - Xiong, Min
AU - Huang, Peixin
AU - Heruth, Daniel P.
AU - Bi, Charlie
AU - Gaedigk, Roger
AU - Jiang, Xun
AU - Li, Ding You
AU - Wyckoff, Gerald
AU - Grigoryev, Dmitry N.
AU - Gao, Li
AU - Li, Linheng
AU - Wu, Min
AU - Steven Leeder, J.
AU - Ye, Shui Qing
N1 - Funding Information:
anonymized pediatric liver samples, ages 0 days to 17 years, were received from the following sources: the NICHD Brain and Tissue Bank at the University of Maryland (funded by NIH contract HHSN275200900011C, Ref. No. #N01-HD-9-0011); the Liver Tissue Cell Distribution System (funded by NIH Contract #N01-DK-7-0004/HHSN267200700004C); and six samples were received from XenoTech, LLC (Lenexa, KS, USA), to whom we are grateful for their generous gift of tissue samples. Thirty-four prenatal human liver samples (57– 196 days, post-conception) were received from an additional NICHD-funded tissue retrieval center, the Central Laboratory for Human Embryology (University of Washington, Seattle, WA, USA). All tissues were flash frozen and maintained at − 80 °C before isolation of DNA and RNA. All the samples were from anonymous, deceased donors, and the use of these tissues was declared as nonhuman subjects research by the University of Missouri-Kansas City Pediatric Health Sciences Review Board.
Funding Information:
Acknowledgements. We thank Marianne N Nsumu and Suman Chaudhary for excellent technical assistance. Our research has been in part supported by National Institutes of Health Grant HL 080042 (SQY), the start-up fund and William R Brown/ Missouri Endowment of The Children’s Mercy Hospitals and University of Missouri at Kansas City (SQY).
Funding Information:
Our research has been in part supported by National Institutes of Health Grant HL 080042
Publisher Copyright:
© The Author(s) 2017.
PY - 2017
Y1 - 2017
N2 - 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 NamptF/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.
AB - 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 NamptF/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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U2 - 10.1038/cddis.2017.132
DO - 10.1038/cddis.2017.132
M3 - Article
C2 - 28333140
AN - SCOPUS:85019886256
VL - 8
JO - Cell Death and Disease
JF - Cell Death and Disease
SN - 2041-4889
IS - 3
M1 - e2705
ER -