The role of the tryptophan-nicotinamide pathway in a 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 (TRP-NAM) pathway and subsequently NAD+ dependent metabolism regulator sirtuin1 (SIRT1). We report that severe malnutrition in weanling mice, induced by feeding a low protein diet, leads to an impaired TRP-NAM pathway and affects hepatic mitochondrial turnover and function. We demonstrate that stimulating the TRP-NAM pathway improves hepatic mitochondrial and overall metabolic function which is dependent on SIRT1. Activating SIRT1 is sufficient to induce improvement in metabolic functions. Our findings indicate that modulating the TRP-NAM pathway can partially improve liver metabolic function in severe malnutrition and could lead to the development of new interventions for children with severe malnutrition.