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Journal of Lipid Research, Vol. 47, 2223-2232, October 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Causes and prevention of tamoxifen-induced accumulation of triacylglycerol in rat liver

Oddrun Anita Gudbrandsen^1,2, Therese Halvorsen Rost¹ and Rolf Kristian Berge

Institute of Medicine, Section of Medical Biochemistry, University of Bergen, Haukeland University Hospital, N-5021 Bergen, Norway

Published, JLR Papers in Press, July 24, 2006.

¹ O. A. Gudbrandsen and T. H. Rost contributed equally to this work.

² To whom correspondence should be addressed. e-mail: nkjgu{at}uib.no

Tamoxifen can induce hepatic steatosis in women. In this study, we wanted to elucidate the mechanism behind the 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 by decreased acetyl-coenzyme A carboxylase (ACC) and 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 compared with 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. In conclusion, tamoxifen increased the hepatic triacylglycerol level, probably as a result of increased triacylglycerol biosynthesis combined with unchanged ß-oxidation. The tamoxifen-induced accumulation of triacylglycerol was prevented by cotreatment with TTA, through mechanisms of increased mitochondrial and peroxisomal ß-oxidation.

Supplementary key words steatosis • lipids • fatty acid catabolism • very low density lipoprotein • peroxisome proliferator-activated receptor

Abbreviations: AADA, arylacetamide deacetylase; ACC, acetyl-coenzyme A carboxylase; ACO, acyl-coenzyme A oxidase; CPT, carnitine palmitoyltransferase; DGAT, diacylglycerol acyltransferase; FAT/CD36, fatty acid translocase; GPAT, glycerol-3-phosphate acyltransferase; L-FABP, liver fatty acid binding protein; PPAR, peroxisome proliferator-activated receptor; SCD-1, stearoyl-coenzyme A desaturase-1; Tam+TTA, combination treatment with tamoxifen and tetradecylthioacetic acid; TTA, tetradecylthioacetic acid

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