The NAD Metabolome is Functionally Depressed in Patients Undergoing Liver Transplantation for Alcohol-related Liver Disease

Abstract

Nicotinamide adenine dinucleotide (NAD+) and related coenzymes play critical roles in liver function. Though hepatic alcohol metabolism depresses NAD+, current understanding of the NAD+ metabolome in alcohol-related liver disease (ArLD) is based on animal models. We used human liver samples to quantify the NAD+ metabolome in ArLD with samples obtained at the time of liver transplantation or resection at University Hospitals Birmingham NHS Foundation Trust (UHB). The severity of steatohepatitis in liver from patients with ArLD was assessed with standard liver function tests (LFT) and histology. NAD-targeted quantitative metabolomic analysis of liver tissue was performed by liquid chromatography-tandem mass spectrometry (LC-MS). Seventy-two human liver specimens were analyzed including 43 with ArLD. The NAD+ metabolome differed significantly between different types of liver disease (two-way ANOVA p = 0.001). ArLD liver tissue showed markedly depressed concentrations of NAD+ (432 μM vs. 616 μM in NL) and precursor molecules nicotinic acid and nicotinamide riboside. There was a significant overall difference in the NAD+ metabolome between ArLD samples with and without steatohepatitis (two-way ANOVA p = 0.018). After correcting for multiple comparisons, a significant difference for individual components of the metabolome was observed for the concentration of NAD+ (mean 451 μM vs. 381 μM, p = 0.045). NAD+ concentration was inversely related to serum bilirubin concentration (r2 −0.127, p = 0.04) and positively correlated with myeloperoxidase activity (r2 0.31, p = 0.003). The concentration of NAD+ and its precursor molecules are significantly reduced in ArLD and are associated with disease activity. Conclusion: Liver samples from people with ArLD show depressed NAD+ and precursor levels as well as depressed myeloperoxidase activity.

Fat mobilization without weight loss is a potentially rapid response to nicotinamide riboside in obese people: it’s time to test with exercise

“…We suggest that a depressed and/or metabolically challenged hepatic NAD metabolome is a potential target for NR interventions, and note that people with alcoholic liver disease have depressed hepatic NAD ( 11 ). It is clearly time to perform trials of longer duration, as well as ones that incorporate physical activity, to test the hypothesis that NR supports mobilization of fat from liver and other storage depots in exercised obese adults.…”

Randomized, placebo-controlled, pilot clinical study evaluating acute Niagen®+ IV and NAD+ IV in healthy adults

“…NAD+ homeostasis is also disturbed in conditions of metabolic stress, including heart failure, diabesity, central and peripheral neurodegeneration, mitochondrial disease, alcoholic liver disease, postpartum, coronavirus infection (Samuel A.J. Trammell et al, 2016;Hamity et al, 2017;Vaur et al, 2017;Diguet et al, 2018;Liu et al, 2018;Ear et al, 2019;Parker et al, 2020;Pirinen et al, 2020;Heer et al, 2021). On the other hand, interventions that boost NAD+ availability have repeatedly been demonstrated to rescue defects associated with the loss of NAD+ homeostasis and improve physiological function (Cantó et al, 2012;Zhang et al, 2016;Martens et al, 2018;Elhassan et al, 2019).…”