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Nicotinamide Riboside, an NAD+ Precursor, Attenuates The Activation of Hepatic Stellate Cells
Author(s) -
Pham Tho X.,
Bae Minkyung,
Lee JiYoung
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.458.5
Subject(s) - hepatic stellate cell , chemistry , nad+ kinase , hepatic fibrosis , extracellular matrix , fibrosis , microbiology and biotechnology , myofibroblast , transforming growth factor , liver injury , biochemistry , endocrinology , medicine , biology , enzyme
Recent evidence suggests that supplementation of nicotinamide riboside (NR), a natural NAD+ precursor found in milk, can reduce liver fibrosis in several mouse models of non‐alcoholic steatohepatitis. However, the molecular mechanism by which NR reduces liver fibrosis remains to be elucidated. Hepatic stellate cells (HSCs) are primarily responsible for the production and deposition of collagen and other extracellular matrix (ECM) substances in the liver during injury. Upon liver injury, HSCs become activated and transdifferentiate into a‐smooth muscle actin (aSMA)‐positive myofibroblasts, which produce ECM proteins such as collagen 1a1 (COL1a1). Therefore, we determined whether the preventive effect of NR on liver fibrosis is attributed to its effect on the activation of HSCs. LX‐2 cells, a human HSC cell line, were pretreated with or without 500 mM of NR for 24 h followed by treatment of 4 ng/mL of transforming growth factor β1 (TGFβ1), a potent pro‐fibrogenic cytokine, for an additional 24 h in the absence or presence of NR. TGFβ1 markedly increased the protein levels of aSMA and COL1a1, while NR pretreatment significantly attenuated the TGFβ1‐induced increase in COL1a1 protein levels. Despite the reduction in COL1a1 protein by NR, its mRNA levels were significantly increased by NR, suggesting that NR may regulate COL1a1 expression at the post‐transcriptional level in LX‐2 cells. We next isolated mouse primary HSCs from C57BL/6 mice and activated them by culturing on a plastic dish for 7 days in the absence or presence of 500 μM NR. Compared to mouse primary HSCs cultured for 2 days, which maintain their quiescent state, HSCs activated for 7 days expressed significantly higher levels of aSMA and COL1a1 mRNA. When NR was added to HSCs during the activation for 7 days, aSMA and COL1a1 mRNA levels were significantly lowered when compared to the cells that were activated in the absence of NR. This suggests that NR treatment attenuated the activation of quiescent mouse primary HSCs to myofibrolasts. Together, we demonstrated that treatment of NR attenuated HSC activation in human and mouse models of HSCs, which suggests that anti‐fibrotic action of NR in the liver may be attributable, at least in part, to its inhibitory effect on the activation of HSCs. Support or Funding Information USDA Hatch CON00972