Nicotinamide riboside protects against liver fibrosis induced by CCl 4 via regulating the acetylation of Smads signaling pathway

Life Sci. 2019 May 15;225:20-28. doi: 10.1016/j.lfs.2019.03.064. Epub 2019 Mar 27.


Aims: Increasing nicotinamide adenine dinucleotide (NAD+) by Nicotinamide riboside (NR) provides protective benefits in multiple disorders. However, the role of NR on liver fibrosis is unclear. We performed in vivo and in vitro experiments to test the hepatic protective effects of NR against liver fibrosis and the underlying mechanisms.

Materials and methods: Mice were injected with CCl4 to establish liver fibrosis model. NR was given by gavage to explore the hepatic protection of NR. LX-2 cells were given a TGF-β stimulation ± NR, the activation of LX-2 cells and the acetylation of Smads were analyzed. To further confirm the role of Sirt1 on the protective pathway of NR, we knockdown Sirt1 in LX-2 cells.

Key findings: We found NR could prevent liver fibrosis and reverse the existing liver fibrosis. NR inhibited the activation of LX-2 cells induced by TGF-β, activated Sirt1 and deacetylated Smad2/3. Sirt1 knockdown diminished the inhibiting effect of NR on LX-2 cells activation, and increased expressions of acetylated Smads. In conclusion, NR could prevent liver fibrosis via suppressing activation of hepatic stellate cells (HSCs). This protective effect was mediated by regulating the acetylation of Smads signaling pathway.

Significance: NR protected mice against liver fibrosis induced by CCl4. NR suppressed activation of hepatic stellate cells induced by TGF-β. NR protects liver fibrosis via increasing the activity of Sirt1 and decreasing the expression of P300, resulting in the deacetylation of Smads in stellate cells.

Keywords: Deacetylation; HSCs; Nicotinamide riboside; P300; Sirt1; TGF-β.

MeSH terms

  • Acetylation
  • Animals
  • Carbon Tetrachloride / toxicity*
  • E1A-Associated p300 Protein / metabolism
  • Gene Expression Regulation
  • Hepatic Stellate Cells / drug effects*
  • Hepatic Stellate Cells / metabolism
  • Hepatic Stellate Cells / pathology
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • Liver Cirrhosis / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Protective Agents / pharmacology*
  • Pyridinium Compounds
  • Sirtuin 1 / metabolism
  • Smad2 Protein / metabolism*
  • Smad3 Protein / metabolism*
  • Transforming Growth Factor beta / metabolism


  • Protective Agents
  • Pyridinium Compounds
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Transforming Growth Factor beta
  • nicotinamide-beta-riboside
  • Niacinamide
  • Carbon Tetrachloride
  • E1A-Associated p300 Protein
  • Ep300 protein, mouse
  • Sirt1 protein, mouse
  • Sirtuin 1