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Vitamin C deficiency attenuates liver fibrosis by way of up‐regulated peroxisome proliferator‐activated receptor‐gamma expression in senescence marker protein 30 knockout mice
Author(s) -
Park JinKyu,
Ki MiRan,
Lee HyeRim,
Hong IlHwa,
Ji AeRi,
Ishigami Akihito,
Park SeIl,
Kim JiMin,
Chung HaeYoung,
Yoo SungEun,
Jeong KyuShik
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23499
Subject(s) - endocrinology , medicine , fibrosis , knockout mouse , hepatic stellate cell , peroxisome proliferator activated receptor , vitamin , hepatic fibrosis , biology , calcitriol receptor , receptor , chemistry , vitamin d and neurology
Senescence marker protein 30 (SMP30), an important aging marker molecule that is highly expressed in the liver, has been known to protect hepatocytes from apoptosis by the synthesis of vitamin C. To explore the function of SMP30 in liver fibrosis, the effect of SMP30 deficiency on liver fibrosis was investigated in SMP30 knockout (KO) mice. Moreover, the in vivo results were further confirmed by way of hepatic stellate cell (HSC) isolation. We demonstrated that carbon tetrachloride (CCl 4 )‐induced liver fibrosis and the nuclear translocation of p‐Smad2/3, the immediate downstream of transforming growth factor beta (TGF‐β), were significantly inhibited in the liver of SMP30 KO mice compared with wildtype (WT) mice. We also confirmed that both WT and SMP30 KO HSCs did not express SMP30. Finally, we further confirmed that up‐regulation of peroxisome proliferator‐activated receptor‐gamma (PPAR‐γ) caused by a lack of vitamin C was the pivotal factor in the mechanisms for attenuated liver fibrosis of SMP30 KO mice, and feeding with vitamin C restored CCl 4 ‐induced liver fibrosis in SMP30 KO mice. Conclusion: Vitamin C deficiency by SMP30 depletion attenuated liver fibrosis by way of up‐regulated PPAR‐γ expression in SMP30 KO mice. Our results provide, for the first time, the possible mechanisms underlying inhibition of HSC activation associated with vitamin C and PPAR‐γ up‐regulation in liver fibrosis of SMP30 KO mice. (H EPATOLOGY 2010.)