Nicotinamide riboside, an NAD+ precursor, attenuates the development of liver fibrosis in a diet-induced mouse model of liver fibrosis

Biochim Biophys Acta Mol Basis Dis. 2019 Sep 1;1865(9):2451-2463. doi: 10.1016/j.bbadis.2019.06.009. Epub 2019 Jun 11.

Abstract

Objective: Liver fibrosis is part of the non-alcoholic fatty liver disease (NAFLD) spectrum, which currently has no approved pharmacological treatment. In this study, we investigated whether supplementation of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD+) precursor, can reduce the development of liver fibrosis in a diet-induced mouse model of liver fibrosis.

Methods: Male C57BL/6 J mice were fed a low-fat control (LF), a high-fat/high-sucrose/high-cholesterol control (HF) or a HF diet supplemented with NR at 400 mg/kg/day (HF-NR) for 20 weeks. Features of liver fibrosis were assessed by histological and biochemical analyses. Whole-body energy metabolism was also assessed using indirect calorimetry. Primary mouse and human hepatic stellate cells were used to determine the anti-fibrogenic effects of NR in vitro.

Results: NR supplementation significantly reduced body weight of mice only 7 weeks after mice were on the supplementation, but did not attenuate serum alanine aminotransferase levels, liver steatosis, or liver inflammation. However, NR markedly reduced collagen accumulation in the liver. RNA-Seq analysis suggested that the expression of genes involved in NAD+ metabolism is altered in activated hepatic stellate cells (HSCs) compared to quiescent HSCs. NR inhibited the activation of HSCs in primary mouse and human HSCs. Indirect calorimetry showed that NR increased energy expenditure, likely by upregulation of β-oxidation in skeletal muscle and brown adipose tissue.

Conclusion: NR attenuated HSC activation, leading to reduced liver fibrosis in a diet-induced mouse model of liver fibrosis. The data suggest that NR may be developed as a potential preventative for human liver fibrosis.

Keywords: Hepatic stellate cells; Liver fibrosis; NAD +; Nicotinamide riboside.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Body Weight / drug effects
  • Collagen / metabolism
  • Diet, High-Fat
  • Dietary Supplements
  • Disease Models, Animal
  • Energy Metabolism / drug effects
  • Hepatic Stellate Cells / cytology
  • Hepatic Stellate Cells / metabolism
  • Humans
  • Liver / drug effects*
  • Liver / metabolism
  • Liver / pathology
  • Mice
  • Mice, Inbred C57BL
  • Muscle, Skeletal / metabolism
  • NAD / metabolism
  • Niacinamide / administration & dosage
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Non-alcoholic Fatty Liver Disease / pathology*
  • Non-alcoholic Fatty Liver Disease / prevention & control

Substances

  • nicotinamide-beta-riboside
  • NAD
  • Niacinamide
  • Collagen