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 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.
Division of Experimental and Translational Genetics, Department of Pediatrics, The Children's Mercy Hospital, University of Missouri - Kansas City School of Medicine, Kansas City, MO, USA.
Li Q
LQ
Zhang
Division of Clinical Pharmacology and Therapeutic Innovation,The Children's Mercy Hospital, Kansas City, MO, USA.
Leon
L
Van Haandel
Division of Experimental and Translational Genetics, Department of Pediatrics, The Children's Mercy Hospital, University of Missouri - Kansas City School of Medicine, Kansas City, MO, USA.
Min
M
Xiong
Division of Experimental and Translational Genetics, Department of Pediatrics, The Children's Mercy Hospital, University of Missouri - Kansas City School of Medicine, Kansas City, MO, USA.
Peixin
P
Huang
Division of Experimental and Translational Genetics, Department of Pediatrics, The Children's Mercy Hospital, University of Missouri - Kansas City School of Medicine, Kansas City, MO, USA.
Daniel P
DP
Heruth
Division of Clinical Pharmacology and Therapeutic Innovation,The Children's Mercy Hospital, Kansas City, MO, USA.
Charlie
C
Bi
Division of Clinical Pharmacology and Therapeutic Innovation,The Children's Mercy Hospital, Kansas City, MO, USA.
Roger
R
Gaedigk
Division of Experimental and Translational Genetics, Department of Pediatrics, The Children's Mercy Hospital, University of Missouri - Kansas City School of Medicine, Kansas City, MO, USA.|Department of Pediatrics, Tangdu Hospital, Fourth Military Medical University, Xian, China.
Xun
X
Jiang
Division of Gastroenterology, Department of Pediatrics, The Children's Mercy Hospital, Kansas City, MO, USA.
Ding-You
DY
Li
Division of Molecular Biology and Biochemistry, University of Missouri School of Biological Sciences, Kansas City, MO, USA.
Gerald
G
Wyckoff
Laboratory of Genitourinary Cancer Pathogenesis, National Cancer Institute, Bethesda, MD, USA.
Dmitry N
DN
Grigoryev
Division of Allergy and Clinical Immunology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Li
L
Gao
Stowers Institute for Medical Research, Kansas City, MO, USA.
Linheng
L
Li
Department of Biomedical Sciences, University of North Dakota, Grand Forks, ND, USA.
Min
M
Wu
Division of Clinical Pharmacology and Therapeutic Innovation,The Children's Mercy Hospital, Kansas City, MO, USA.
J Steven
JS
Leeder
Division of Experimental and Translational Genetics, Department of Pediatrics, The Children's Mercy Hospital, University of Missouri - Kansas City School of Medicine, Kansas City, MO, USA.|Department of Biomedical and Health Informatics, University of Missouri - Kansas City School of Medicine, Kansas City, MO, USA.
Shui Qing
SQ
Ye
D000293:Adolescent; D000818:Animals; D002648:Child; D002675:Child, Preschool; D002952:Citric Acid Cycle / Q000502:physiology; D016207:Cytokines / Q000378:metabolism*; D053595:Embryonic Stem Cells / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000201:enzymology; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD; D009369:Neoplasms / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D059467:Transcriptome / Q000502:physiology; D014280:Triglycerides / Q000378:metabolism
D016207:Cytokines; D005231:Fatty Acids, Unsaturated; D014280:Triglycerides; D009243:NAD; D054409:Nicotinamide Phosphoribosyltransferase; C495867:nicotinamide phosphoribosyltransferase, mouse