Ascorbate promotes carbon tetrachloride-induced hepatic injury in senescence marker protein 30-deficient mice by enhancing inflammation.
The genetic deletion of the senescence marker protein 30 (SMP30) gene results in ascorbate deficiency and the premature aging processes in mice. Apparent liver injury of SMP30(-/-) mice was less severe than those of wild type (WT) mice, upon chronic CCl(4) injection. The purpose of this study was to investigate the pathophysiology underlying the mild CCl(4) toxicity in SMP30(-/-) mice. Along with the lower level of serum alanine aminotransferase, the livers of SMP30(-/-) mice revealed a lesser glycogen depletion, a decrease in c-Jun N-terminal kinase (JNK)-mediated inflammatory signaling in parallel with tumor necrosis factor-alpha and interleukin-1 beta, inducible nitric oxide synthase and glutathione peroxidase, and the lower lipid peroxidation as compared to those of WT mice. CCl(4)-induced proliferation, measured by the expression of proliferating cell nuclear antigen, was low in SMP30(-/-) mice as compared with that of WT mice whereas the levels of p21 and Bax were comparable to those of the CCl(4)-treated WT mice. Moreover, CCl(4) toxicity in ascorbate-fed SMP30(-/-) mice was comparable to that of the CCl(4)-alone treated WT mice, accompanied by an increase in the above mentioned factors. Conversely, ascorbate partly compensated for the CCl(4)-induced oxidative stress in WT mice, indicating that sufficient ascorbate may be required for an antioxidant function under severe levels of oxidative stress. Our data suggest that the restoration of ascorbate-deficiency reverses a sluggish immune system into an activated condition by an increase in JNK-mediated inflammation and free radical cascade; thus leading to accelerated hepatic damage in SMP30(-/-) mice.
Ki
Mi-Ran
MR
Department of Pathology, College of Veterinary Medicine, Kyungpook National University, 702-701, Daegu, South Korea.
Lee
Hye-Rim
HR
Park
Jin-Kyu
JK
Hong
Il-Hwa
IH
Han
Seon-Young
SY
You
Sang-Young
SY
Lee
Eun-Mi
EM
Kim
Ah-Young
AY
Lee
Seung-Sook
SS
Jeong
Kyu-Shik
KS
D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D001205:Ascorbic Acid / Q000378:metabolism / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D002251:Carbon Tetrachloride / Q000633:toxicity; D002252:Carbon Tetrachloride Poisoning / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D018384:Oxidative Stress; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
D000975:Antioxidants; D002135:Calcium-Binding Proteins; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; C513324:Rgn protein, mouse; D014409:Tumor Necrosis Factor-alpha; D002251:Carbon Tetrachloride; D048031:JNK Mitogen-Activated Protein Kinases; D001205:Ascorbic Acid