Vitamin C deficiency attenuates liver fibrosis by way of up-regulated peroxisome proliferator-activated receptor-gamma expression in senescence marker protein 30 knockout mice.
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-beta), 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-gamma) 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.


CONCLUSIONS
Vitamin C deficiency by SMP30 depletion attenuated liver fibrosis by way of up-regulated PPAR-gamma 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-gamma up-regulation in liver fibrosis of SMP30 KO mice.
Park
Jin-Kyu
JK
College of Veterinary Medicine, Kyungpook National University, Daegu, Republic of Korea.
Ki
Mi-Ran
MR
Lee
Hye-Rim
HR
Hong
Il-Hwa
IH
Ji
Ae-Ri
AR
Ishigami
Akihito
A
Park
Se-Il
SI
Kim
Ji-Min
JM
Chung
Hae-Young
HY
Yoo
Sung-Eun
SE
Jeong
Kyu-Shik
KS
D000818:Animals; D001205:Ascorbic Acid / Q000097:blood / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency*; D002252:Carbon Tetrachloride Poisoning / Q000473:pathology; D055166:Hepatic Stellate Cells / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency*; D008103:Liver Cirrhosis / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000378:metabolism*; D051785:Smad Proteins / Q000378:metabolism
D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D047495:PPAR gamma; C513324:Rgn protein, mouse; D051785:Smad Proteins; D001205:Ascorbic Acid