The Role of Tryptophan-Nicotinamide (TRP-NAM) Pathway in Malnutrition Induced Liver Dysfunction

Abstract

Abstract Objectives Malnutrition contributes to 45% of the deaths of children < 5. Mortality in severe malnutrition is often related to metabolic disturbances, including hypoglycemia, indicating hepatic metabolic dysfunction. Children with severe malnutrition have been found to have significantly lower circulating tryptophan (TRP) levels in their blood. Disturbances in TRP-NAM pathway have been implicated in liver and intestine diseases, potentially mediated by NAD-dependent deacetylase SIRT1. This study aim to evaluate the effect of modulating TRP-NAM pathway on hepatic metabolism dysfunction in a mouse model of severe malnutrition. Methods Weanling male C57BL/6J mice were randomized into different groups fed with a control diet (18% protein), or a malnourished diet (1% protein) with or without supplementation of modulators of the TRP-NAM pathway (NAM, NR and TRP). Supplementation therapies were given from days 7–14 after start of the dietary intervention. In addition, SIRT1 modulators treatment including resveratrol, EX-527 and vehicle were tested. Comprehensive metabolic, histological and molecular analyses were performed. Results After diet treatment, the mice in the 1% protein group had significantly lower body weight and body length compared to the 18% protein group, without any effect of modulators of the TRP-NAM pathway. Feeding mice a 1% protein diet led to severe hepatic steatosis, mitochondrial structural alterations, lower ATP levels, disrupted TRP-NAM pathway metabolites, and a decrease of phospholipids to triglycerides ratio. NAM, NR and TRP treatment all led to a partial reversal of the hepatic steatosis in the 1% protein-fed mice. ATP levels, mtDNA copy number, and PPARα target genes in the β-oxidation pathway were also recovered in treatment group. We postulate that the effect is mediated through changes in levels of NAD+, which is critical in redox reactions and is a substrate for SIRT1, important for mitochondrial function. Conclusions Modulating TRP-NAM pathway can partially improve liver metabolic function in a mouse model of severe malnutrition. This study improves our understanding of the cellular pathophysiology of severe malnutrition. The results of this project could lead to the development of new interventions which could then be taken to clinical trials. Funding Sources Bill & Melinda Gates Foundation.