NAD and NAFLD - caution, causality and careful optimism.

The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide, and new treatments are sorely needed. Nicotinamide adenine dinucleotide (NAD ) has been proposed as a potential target to prevent and reverse NAFLD. NAD is an important redox factor for energy metabolism and is used as a substrate by a range of enzymes, including sirtuins (SIRT), which regulates histone acetylation, transcription factor activity and mitochondrial function. NAD is also a precursor for reduced nicotinamide adenine dinucleotide phosphate (NADPH), which is an important component of the antioxidant defense system. NAD precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are available as over-the-counter dietary supplements, and oral supplementation with these precursors increases hepatic NAD levels and prevents hepatic lipid accumulation in pre-clinical models of NAFLD. NAD precursors have also been found to improve hepatic mitochondrial function and decrease oxidative stress in pre-clinical NAFLD models. NAD repletion also prevents NAFLD progression to non-alcoholic steatohepatitis (NASH), as NAD precursor supplementation is associated with decreased hepatic stellate cell activation, and decreased fibrosis. However, initial clinical trials have only shown modest effects when NAD precursors were administrated to people with obesity. We review the available pre-clinical investigations of NAD supplementation for targeting NAFLD, and discuss how data from the first clinical trials can be reconciled with observations from preclinical research.