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.