The role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction

Guanlan Hu, Catriona Ling, Lijun Chi, Mehakpreet K. Thind, Samuel Furse, Albert Koulman, Jonathan R. Swann, Dorothy Lee, Marjolein M. Calon, Celine Bourdon, Christian J. Versloot, Barbara M. Bakker, Gerard Bryan Gonzales, Peter K. Kim and Robert H. J. Bandsma ()
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Guanlan Hu: University of Toronto
Catriona Ling: University of Toronto
Lijun Chi: The Hospital for Sick Children
Mehakpreet K. Thind: University of Toronto
Samuel Furse: University of Cambridge
Albert Koulman: University of Cambridge
Jonathan R. Swann: University of Southampton
Dorothy Lee: The Hospital for Sick Children
Marjolein M. Calon: The Hospital for Sick Children
Celine Bourdon: The Hospital for Sick Children
Christian J. Versloot: University of Groningen, University Medical Center Groningen
Barbara M. Bakker: University of Groningen, University Medical Center Groningen
Gerard Bryan Gonzales: The Hospital for Sick Children
Peter K. Kim: University of Toronto
Robert H. J. Bandsma: University of Toronto

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Mortality in children with severe malnutrition is strongly related to signs of metabolic dysfunction, such as hypoglycemia. Lower circulating tryptophan levels in children with severe malnutrition suggest a possible disturbance in the tryptophan-nicotinamide adenine dinucleotide (TRP-NAD+) pathway and subsequently in NAD+ dependent metabolism regulator sirtuin1 (SIRT1). Here we show that severe malnutrition in weanling mice, induced by 2-weeks of low protein diet feeding from weaning, leads to an impaired TRP-NAD+ pathway with decreased NAD+ levels and affects hepatic mitochondrial turnover and function. We demonstrate that stimulating the TRP-NAD+ pathway with NAD+ precursors improves hepatic mitochondrial and overall metabolic function through SIRT1 modulation. Activating SIRT1 is sufficient to induce improvement in metabolic functions. Our findings indicate that modulating the TRP-NAD+ pathway can improve liver metabolic function in a mouse model of severe malnutrition. These results could lead to the development of new interventions for children with severe malnutrition.

Date: 2022
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DOI: 10.1038/s41467-022-35317-y

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