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 M vs. 616 M 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 M vs. 381 M, 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.