The Role of Tryptophan‐Nicotinamide (TRP‐NAM) Pathway in Malnutrition Induced Liver Dysfunction
Bibliographic record
Abstract
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
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".