Submitted on March 30, 2006
Revised on July 6, 2006
Accepted on July 24, 2006
Causes and prevention of tamoxifen-induced accumulation of triacylglycerol in rat liver
Oddrun A. Gudbrandsen, Therese H. Røst, and Rolf K. Berge
Institute of Medicine, University of Bergen, Bergen 5021
Corresponding Author: nkjgu{at}uib.no
Tamoxifen can induce steatosis in women. In the present study we wanted to elucidate the mechanism behind tamoxifen-induced accumulation of triacylglycerol in liver in female rats, and we hoped to prevent this development by combination treatment with the modified fatty acid tetradecylthioacetic acid (TTA). The increased hepatic triacylglycerol level after tamoxifen treatment was accompanied with decreased acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) activities, increased glycerol-3-phosphate acyltransferase (GPAT) activity, and a tendency to increased diacylglycerol acyltransferase (DGAT) activity. The activities and mRNA levels of enzymes involved in ß-oxidation, ketogenesis and uptake of lipids from liver were unaffected by tamoxifen, whereas the uptake of lipoproteins was unchanged and the uptake of fatty acids was decreased. Combination treatment with tamoxifen and TTA (Tam+TTA) normalized the hepatic triacylglycerol level and increased the activities of ACC, FAS, GPAT and DGAT when compared to tamoxifen treated rats. The activities and mRNA levels of enzymes involved in ß-oxidation, ketogenesis and uptake of lipids were increased after Tam+TTA treatment. Conclusions: Tamoxifen increased the hepatic triacylglycerol level, probably due to increased triacylglycerol biosynthesis combined with unchanged ß-oxidation. The tamoxifen-induced accumulation of triacylglycerol was prevented by co-treatment with TTA, through mechanisms of increased mitochondrial and peroxisomal ß-oxidation.
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