Pioglitazone retrieves hepatic antioxidant DNA repair in a mice model of high fat diet.
BACKGROUND
Pioglitazone was reported to improve hepatic steatosis and necroinflammation in human studies. To investigate whether the hepato-protective effect of pioglitazone was associated with an improvement of antioxidant defense mechanism, oxidative DNA damage and repair activity were determined in a high fat diet model. Male C57BL/6 mice were respectively fed with a 30% fat diet, the same diet with pioglitazone 100 mg/kg/day, or a chow diet as control for 8 weeks. Tissue oxidative stress was indicated by malondialdehyde concentration. Oxidative DNA damage was detected by immunohistochemical 8-oxoG staining. Enzymatic antioxidant defense was detected by the real-time PCR of superoxide dismutase (Sod1, Sod2) and DNA glycosylase (Ogg1, MutY). Oxidative DNA repair was detected by immunohistochemical staining and western blotting of OGG1 expression.


RESULTS
Our results show that hepatic steatosis was induced by a high-fat diet and improved by adding pioglitazone. Malondialdehyde concentration and 8-oxoG staining were strongly increased in the high-fat diet group, but attenuated by pioglitazone. Gene expressions of antioxidant defense mechanism: Sod1, Sod2, Ogg1 and MutY significantly decreased in the high-fat diet group but reversed by pioglitazone co-administration.


CONCLUSIONS
The attenuation of hepatic oxidative DNA damage by pioglitazone in a high-fat diet may be mediated by up-regulation of the antioxidant defense mechanism and oxidative DNA repair activity. The diminution of oxidative damage may explain the clinical benefit of pioglitazone treatment in patients with non-alcoholic fatty liver disease.
Hsiao
Pi-Jung
PJ
Division of Endocrinology and Metabolism, Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan. pjhsiao@cc.kmu.edu.tw
Hsieh
Tusty-Jiuan
TJ
Kuo
Kung-Kai
KK
Hung
Wei-Wen
WW
Tsai
Kun-Bow
KB
Yang
Ching-Hsiu
CH
Yu
Ming-Lung
ML
Shin
Shyi-Jang
SJ
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair; D004041:Dietary Fats / Q000008:administration & dosage*; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology*; D006151:Guanosine / Q000031:analogs & derivatives / Q000737:chemistry; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D000077205:Pioglitazone; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D045162:Thiazolidinediones / Q000627:therapeutic use*; D000099156:Superoxide Dismutase 2
D000975:Antioxidants; D045647:DNA Glycosylases; D004041:Dietary Fats; D006151:Guanosine; D007004:Hypoglycemic Agents; D008315:Malondialdehyde; D000077205:Pioglitazone; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D045162:Thiazolidinediones; D000099156:Superoxide Dismutase 2; C000606290:SOD1 protein, human; C046215:8-hydroxyguanosine; C000606291:Sod1 protein, mouse; C485990:Ogg1 protein, mouse; C061738:mutY adenine glycosylase