Personal model‐assisted identification of NAD⁺ and glutathione metabolism as intervention target in NAFLD

Abstract

To elucidate the molecular mechanisms underlying non‐alcoholic fatty liver disease (NAFLD), we recruited 86 subjects with varying degrees of hepatic steatosis (HS). We obtained experimental data on lipoprotein fluxes and used these individual measurements as personalized constraints of a hepatocyte genome‐scale metabolic model to investigate metabolic differences in liver, taking into account its interactions with other tissues. Our systems level analysis predicted an altered demand for NAD + and glutathione (GSH) in subjects with high HS. Our analysis and metabolomic measurements showed that plasma levels of glycine, serine, and associated metabolites are negatively correlated with HS, suggesting that these GSH metabolism precursors might be limiting. Quantification of the hepatic expression levels of the associated enzymes further pointed to altered de novo GSH synthesis. To assess the effect of GSH and NAD+ repletion on the development of NAFLD, we added precursors for GSH and NAD + biosynthesis to the Western diet and demonstrated that supplementation prevents HS in mice. In a proof‐of‐concept human study, we found improved liver function and decreased HS after supplementation with serine (a precursor to glycine) and hereby propose a strategy for NAFLD treatment.

Challenges and emergent solutions for LC‐MS/MS based untargeted metabolomics in diseases

“…LC‐MS‐based metabolomics have revolutionized the study of small molecules, and has been applied to the study of acute and chronic diseases, nutrition, biomarker discovery, microbiology, metabolic/endocrine disorders, and precision medicine, which is a concept to tailor medical treatment based on an individual patient disease molecular characteristics. Due to its high sensitivity, versatility, and no need for chemical derivatization, and with the introduction of new ionization techniques, LC‐MS/MS‐based metabolomics has gained popularity in recent years .…”

“…The ability to capture and map the global composition and quantitative changes in the metabolome offered by the major analytical platforms of nuclear magnetic resonance (NMR), gas chromatography (GC-MS), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) have provided enhanced coverage of the metabolome space in biology, medicine, and biotechnology. [6][7][8] LC-MS-based metabolomics have revolutionized the study of small molecules, and has been applied to the study of acute and chronic diseases, 9,10 nutrition, 11,12 biomarker discovery, 3,14 microbiology, 15,16 metabolic/endocrine disorders, 17,18 and precision medicine, 19,20 which is a concept to tailor medical treatment based on an individual patient disease molecular characteristics. Due to its high sensitivity, versatility, and no need for chemical derivatization, and with the introduction of new ionization techniques, 21,22 LC-MS/MS-based metabolomics has gained popularity in recent years.…”

Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance

“…In addition to BCAAs and AAAs, other AAs, such as glutamate, glutamine, alanine, and aspartate, have been found to be positively associated with increased cardiometabolic risk and particularly with Hep-IR, (12,(17)(18)(19) while glycine and serine were found decreased in metabolic diseases, including NAFLD. (19)(20)(21)(22)(23) Thus, the first aim of our study was to evaluate if plasma AA concentrations were increased/decreased similarly in subjects with and without obesity but with NAFLD and their association with the degree of fasting Hep-IR and peripheral IR. Our second aim was to evaluate if alterations in plasma AA concentrations (such as BCAAs, AAAs, glutamate, glycine, and serine), which alter cell function or are involved in mitochondrial function and oxidative stress, might reflect hepatic inflammation and/ or fibrosis.…”

Emerging Applications of Metabolomics in Clinical Pharmacology

“…Furthermore, they revealed that mammalian target of rapamycin complex 1–regulated S‐adenosylmethionine decarboxylase 1 was upstream of the metabolic reprogramming involved in prostate cancer. Another metabolomics study of hepatic steatosis in patients identified glutathione and nicotinamide adenine dinucleotide metabolism as potential intervention targets in non‐alcoholic fatty liver disease …”

“…Another metabolomics study of hepatic steatosis in patients identified glutathione and nicotinamide adenine dinucleotide metabolism as potential intervention targets in nonalcoholic fatty liver disease. 60 The emerging role of metabolomics combined with other -omics, such as genomics, in elucidating disease mechanisms has been recognized as well. To comprehensively understand the mechanism underlying the human immune responses to Zostavax vaccination, Li et al 61 established a multiscale, multifactorial response network by integrating metabolomics, transcriptomics, flow cytometry, and plasma cytokine data sets.…”