Abstract
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 beta-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 beta-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 beta-oxidation. The tamoxifen-induced accumulation of triacylglycerol was prevented by cotreatment with TTA, through mechanisms of increased mitochondrial and peroxisomal beta-oxidation.
Highlights
Tamoxifen can induce hepatic steatosis in women
Tamoxifen treatment is associated with an increased risk of the development of nonalcoholic fatty liver [2,3,4], and it is reported that as many as 43% of women with breast cancer treated with tamoxifen may develop steatosis within the first 2 years of treatment [4]
We had two aims: first, we wanted to elucidate the mechanisms behind the accumulation of triacylglycerol in liver of female rats treated with tamoxifen; second, we wanted to investigate whether cotreatment with the modified fatty acid tetradecylthioacetic acid (TTA) could abolish this undesirable side effect of tamoxifen
Summary
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 activities and mRNA levels of enzymes involved in b-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 (Tam1TTA) normalized the hepatic triacylglycerol level and increased the activities of ACC, FAS, GPAT, and DGAT compared with tamoxifentreated rats. The activities and mRNA levels of enzymes involved in b-oxidation, ketogenesis, and uptake of lipids were increased after Tam1TTA treatment. The tamoxifen-induced accumulation of triacylglycerol was prevented by cotreatment with TTA, through mechanisms of increased mitochondrial and peroxisomal b-oxidation.—Gudbrandsen, O. To clarify the mechanisms involved, we measured the activities and gene expression of enzymes controlling the hepatic biosynthesis, b-oxidation, secretion, and uptake of lipids and quantified several products of these pathways
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