NAD+ and NAFLD - caution, causality and careful optimism

J Physiol. 2022 Mar;600(5):1135-1154. doi: 10.1113/JP280908. Epub 2021 May 27.

Abstract

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.

Keywords: NAD+ salvage; NAFLD; NAMPT; NASH; nicotinamide; nicotinamide riboside.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Dietary Supplements
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • NAD / metabolism
  • Non-alcoholic Fatty Liver Disease* / metabolism

Substances

  • NAD