Effects of rosiglitazone on the liver histology and mitochondrial function in ob/ob mice.
Insulin resistance is present in almost all patients with nonalcoholic steatohepatitis (NAFLD), and mitochondrial dysfunction likely plays a critical role in the progression of fatty liver into nonalcoholic steatohepatitis. Rosiglitazone, a selective ligand of peroxisome proliferator-activated receptor gamma (PPARgamma), is an insulin sensitizer drug that has been used in a number of insulin-resistant conditions, including NAFLD. The aim of this study was to analyze the effects of rosiglitazone on the liver histology and mitochondrial function in a model of NAFLD. All studies were carried out in wild-type and leptin-deficient (ob/ob) C57BL/6J mice. Ob/ob mice were treated with 1 mg/kg/day, and activity of mitochondrial respiratory chain (MRC), beta-oxidation, lipid peroxidation, glutathione content in mitochondria, and 3-tyrosine-nitrated proteins in mitochondria were measured. In addition, histological and ultrastructural changes induced by rosiglitazone were also noted. Rosiglitazone treatment increased liver steatosis, particularly microvesicular steatosis. In these animals, mitochondria were markedly swollen with cristae peripherally placed. In ob/ob mice, this drug increased PPARgamma protein expression and lipid peroxide content in liver tissue and decreased glutathione concentration in mitochondria. Rosiglitazone suppressed the activity of complex I of the MRC in ob/ob mice, but did not affect beta-oxidation. 3-Tyrosine nitrated mitochondrial proteins, significantly increased in ob/ob mice, were not modified by rosiglitazone treatment.


CONCLUSIONS
Treatment of ob/ob mice with rosiglitazone did not reverse histological lesions of NAFLD or improve MRC activity. On the contrary, rosiglitazone reduced activity of complex I and increased oxidative stress and liver steatosis.
García-Ruiz
Inmaculada
I
Research Center, Hospital Universitario 12 de Octubre, Madrid, Spain.
Rodríguez-Juan
Cristina
C
Díaz-Sanjuán
Teresa
T
Martínez
Miguel Angel
MA
Muñoz-Yagüe
Teresa
T
Solís-Herruzo
José A
JA
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D005234:Fatty Liver / Q000188:drug therapy / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008854:Microscopy, Electron; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000032:analysis; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis
D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C002744:3-nitrotyrosine; D014443:Tyrosine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase