Antioxidants vitamin E and 1-aminobenzotriazole prevent experimental non-alcoholic steatohepatitis in mice.
OBJECTIVE
Hepatic oxidative stress plays a key role in the development of non-alcoholic steatohepatitis (NASH). However, the protective effects of antioxidants on NASH are largely unknown. The aim of this study was to elucidate the effect and mechanism of antioxidants on NASH in mice.


METHODS
C57BL6/J mice were fed a methionine-choline-deficient (MCD) diet for 10 days or 3 weeks to induce steatohepatitis. Antioxidants (vitamin E, ABT, or vitamin E plus ABT) were supplemented in mice fed a MCD diet, respectively. The effect of antioxidants on oxidative stress and apoptosis was assessed, and activation of adiponectin and expressions of inflammatory factors, apoptosis-related genes, and fibrosis-related genes were assayed.


RESULTS
MCD feeding in mice showed increasing serum alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) levels, and progressive hepatic injury including hepatic steatosis and inflammatory infiltration. Administration of antioxidants vitamin E and/or ABT significantly lowered serum ALAT and ASAT levels (p<0.001) and ameliorated hepatic steatosis and necroinflammation. These effects were associated with repressed hepatic lipid peroxides through reducing hepatic MDA content and enhancing hepatic superoxide dismutase (SOD) activity; down-regulated inflammatory factor COX-2, lowered activity of NF-kappaB, up-regulated anti-apoptotic gene Bcl-2, and down-regulated pro-apoptotic gene Bax suppressed expression of the fibrotic genes TGF-beta1 and MMP2. Moreover, expression of the anti-inflammatory factor adiponectin was also induced by vitamin E or ABT. A combination of vitamin E and ABT showed an additive effect on preventing liver injury.


CONCLUSIONS
The present study provides morphological and molecular biological evidence for the protective role of the antioxidant vitamins E and ABT in ameliorating oxidative stress, hepatic apoptosis, and necroinflammation in experimental nutritional steatohepatitis.
Nan
Yue-Min
YM
Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Shijiazhuang, China. nanyuemin@163.com
Wu
Wen-Juan
WJ
Fu
Na
N
Liang
Bao-Li
BL
Wang
Rong-Qi
RQ
Li
Liang-Xiao
LX
Zhao
Su-Xian
SX
Zhao
Jing-Min
JM
Yu
Jun
J
D000410:Alanine Transaminase / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D015153:Blotting, Western; D051546:Cyclooxygenase 2 / Q000097:blood; D005234:Fatty Liver / Q000097:blood / Q000517:prevention & control*; D019254:Genes, bcl-2 / Q000187:drug effects; D007249:Inflammation / Q000517:prevention & control; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D052002:NF-kappa B p50 Subunit / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology*; D014810:Vitamin E / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000187:drug effects
D000975:Antioxidants; C494827:Bax protein, mouse; D052002:NF-kappa B p50 Subunit; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1; D014230:Triazoles; D051028:bcl-2-Associated X Protein; D014810:Vitamin E; C073701:Nfkb1 protein, mouse; C033020:1-aminobenzotriazole; D051546:Cyclooxygenase 2; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D020778:Matrix Metalloproteinase 2