Pro-oxidant-mediated hepatic fibrosis and effects of antioxidant intervention in murine dietary steatohepatitis.
The mechanistic significance of oxidative stress to fibrogenesis in the methionine and choline-deficient (MCD) diet-induced model of steatohepatitis was evaluated by antioxidant intervention, using either vitamin E or L-2-oxothiazolidine-4-carboxylate (OTC), a cysteine precursor that promotes glutathione synthesis. Significant depletion of hepatic reduced glutathione (GSH) and elevation of thiobarbituric acid reactive substances (TBARS) occurred from week 3 in association with hepatic injury in mice fed the MCD diet. Hepatic stellate cell (HSC) activation and increased collagen alpha1(I) mRNA expression, together with morphologic fibrosis were evident from week 5. Vitamin E repleted GSH, reduced TBARS, steatosis, inflammation, HSC activation and collagen alpha1(I) mRNA expression, and ameliorated fibrosis. Vitamin E did not effect the expression of either profibrogenic cytokines (transforming growth factor-beta 1, connective tissue growth factor) or matrix remodeling enzymes (tissue inhibitor of metalloproteinase-1 and -2, matrix metalloproteinase-2 and -13). Despite repletion of hepatic GSH in OTC-supplemented mice, the initial benefit in the reduction of hepatic TBARS and inhibition of collagen alpha1(I) mRNA expression at week 5, failed to protect these mice from hepatic injury or fibrosis at later time points. Oxidative stress or products of lipid peroxidation mediate HSC activation and collagen gene expression directly in the MCD model of steatohepatitis. Vitamin E but not glutathione augmentation can interrupt this pathogenic process.
Phung
Nghi
N
Storr Liver Unit, Westmead Millennium Institute, University of Sydney at Westmead Hospital, Westmead, NSW 2145, Australia.
Pera
Natasha
N
Farrell
Geoffrey
G
Leclercq
Isabelle
I
Hou
Jing Yun
JY
George
Jacob
J
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D002794:Choline / Q000008:administration & dosage; D016207:Cytokines / Q000235:genetics; D004032:Diet; D015870:Gene Expression / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D006505:Hepatitis / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics; D008715:Methionine / Q000008:administration & dosage; D051379:Mice; D008810:Mice, Inbred C57BL; D011761:Pyrrolidonecarboxylic Acid / Q000008:administration & dosage / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053778:Thiazolidines / Q000008:administration & dosage / Q000494:pharmacology; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism*; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics; D014810:Vitamin E / Q000008:administration & dosage / Q000494:pharmacology
D000975:Antioxidants; D016207:Cytokines; D012333:RNA, Messenger; D053778:Thiazolidines; D017392:Thiobarbituric Acid Reactive Substances; D019714:Tissue Inhibitor of Metalloproteinases; D014810:Vitamin E; D008715:Methionine; D020782:Matrix Metalloproteinases; D005978:Glutathione; D002794:Choline; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid