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The Role of Tryptophan‐Nicotinamide (TRP‐NAM) Pathway in Malnutrition Induced Liver Dysfunction
Author(s) -
Hu Guanlan,
Ling Catriona,
Chi Lijun,
Furse Samuel,
Koulman Albert,
Bandsma Robert
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.08970
Subject(s) - nicotinamide , medicine , tryptophan , endocrinology , nad+ kinase , quinolinic acid , pellagra , niacin , sirtuin 1 , niacinamide , nicotinamide adenine dinucleotide , malnutrition , sirtuin , biology , chemistry , biochemistry , amino acid , enzyme , downregulation and upregulation , gene
Background Malnutrition contributes to 45% of the death of children under 5 years of age. Mortality in severe malnutrition is often related to metabolic disturbances, including hypoglycemia, indicating hepatic metabolic dysfunction. However, the underlying pathophysiology is poorly understood. Children with complicated severe malnutrition have been found to have significantly lower circulating tryptophan levels in their blood. Disturbances in the tryptophan‐nicotinamide pathway have been implicated in liver and other organ diseases, potentially mediated by NAD‐dependent deacetylase sirtuin‐1 (SIRT1). However, there have been no studies that have evaluated the role of tryptophan‐nicotinamide pathway in severe malnutrition. Objectives To evaluate the effect of modulating the tryptophan‐nicotinamide 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 malnutrition‐inducing diet (1% protein) with or without supplementation of modulators of the tryptophan‐nicotinamide pathway (nicotinamide, nicotinamide‐riboside and tryptophan). In addition, SIRT1 modulators treatment including resveratrol, EX‐527 and vehicle were tested. Comprehensive metabolic, histological and molecular analyses were performed. Result After diet treatment, the mice in the 1% protein diet group had significantly lower body weight and length than in the 18% protein group, without any effect of modulators of the tryptophan‐nicotinamide pathway. Feeding mice with a 1% 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. Nicotinamide, nicotinamide‐riboside and tryptophan 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 nicotinamide adenine dinucleotide (NAD+), which is critical in redox reactions and is a substrate for SIRT1, important for mitochondrial function. Significance Modulating TRP‐NAM pathway can partially improve liver metabolic function in a mouse model of severe malnutrition. This study will improve our understanding of the pathophysiology of severe malnutrition. The results of this project could lead to the development of new interventions aimed at improving metabolic disturbances in children with severe malnutrition, which could then be taken to clinical trials. Support or Funding Information Bill & Melinda Gates Foundation