Long-term treatment with metformin in the prevention of fatty liver in Zucker diabetic fatty rats.

Background: Treatment with metformin, the biguanide of hepatic insulin sensitizer, in patients with non-alcoholic fatty liver disease (NAFLD) has been reported with contradictory findings regarding the effectiveness on blood lipids and liver histology. In this study, we aimed to explore the preventive effects of metformin on NAFLD in Zucker diabetic fatty (ZDF) rats.

Methods: Male ZDF rats and Zucker lean rats aged 4-8 weeks were subjected to vehicle or metformin treatment for 6 months. Liver cDNA microarray assay, and protein semiquantitative and histological examinations were performed.

Results: Data demonstrated that ZDF rats developed hyperglycemia, hyperlipidemia, liver deficiency and hepatocyte degeneration. The metformin treatment significantly reduced post-load blood glucose levels, but not blood lipid profiles or liver enzyme levels. Hepatocyte degeneration was not attenuated after the treatment. The metformin-treated ZDF rats showed activation of AMP-activated protein kinase by Western blot and overexpression of cytochrome c oxidase by immunofluorescent microscopy. Gene expression microarray assay demonstrated that a panel of genes participating in glucose and lipid metabolisms were changed in the ZDF rats, and most of the altered genes involved in glucose and cholesterol metabolisms, but not those in fatty acid metabolisms, were corrected by the metformin treatment. No genes associated with inflammation, apoptosis, fibrosis, or cell death were overexpressed in the metformin-treated ZDF rats.

Conclusions: These results suggest that long-term metformin treatment presents no preventive effect for NAFLD in ZDF rats.