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

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.

Suboptimal refeeding compensates stunting in a mouse model of juvenile malnutrition

“…It is well known that severe acute malnutrition affects glucose homeostasis in infants (4,36), a feature that persists later in life (37,38). Furthermore, studies in rodents have shown that post-weaning PEM induces hepatic alterations, such as steatosis and impaired hepatic mitochondrial turnover (39–41). Interestingly, two independent studies using a high-fat diet (58% kcal from fat) after LPD have shown that PEM after weaning does not potentiate fat accumulation, hepatic steatosis and insulin resistance in adult young mice (39,42).…”

A Murine Model of Maternal Micronutrient Deficiencies and Gut Inflammatory Host-microbe Interactions in the Offspring

“… 35 , 54 , 55 A low-protein diet, where 1% of total calories come from protein sources, reduces mitochondrial complexes I, IV, and V expression in mice, causing hepatic steatosis by inhibiting nicotinamide adenine dinucleotide-dependent sirtunin activity. 56 Mitochondrial dysfunction in the offspring may arise from inefficient vertical transfer of nutrients or via inheritance of epigenetic changes occurring during pregnancy. 54 , 57 , 58 , 59 , 60 In a recent human study conducted on mother-infant pairs in Germany, maternal vitamin B12 and folic acid levels significantly correlated with corresponding micronutrients in the offspring.…”

β-Nicotinamide mononucleotide activates NAD+/SIRT1 pathway and attenuates inflammatory and oxidative responses in the hippocampus regions of septic mice

“…The raised expression of NAMPT, involving in the NAD + salvage pathway as the rate-limiting enzyme, and indole-2,3-dioxygenase 1 (IDO1), mediating NAD + de novo synthesis pathways, which might be required for the maintenance of depleted NAD+ and to supply the production of pro-inflammatory factors in sepsis. The supplementation of NAD + precursor could restore the overexpression of genes involved in these pathways, also affect the tryptophan and kynurenine metabolic pathways during NAD + de novo synthesis, and improve cellular immunomodulatory capacity [ 30 , 70 , 71 ]. Poly-adenosine diphosphate-ribose polymerases (PARPs) is a nuclear chromatin-associated protein, which function as an enzyme, could catalyze the transfer of ADP-ribose units from its substrate NAD + covalently to itself and other nuclear chromatin-associated proteins.…”