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

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 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. In conclusion, tamoxifen increased the hepatic triacylglycerol level, probably as a result of increased triacylglycerol biosynthesis combined with unchanged b-oxidation. The tamoxifen-induced accumulation of triacylglycerol was prevented by cotreatment with TTA, through mechanisms of increased mitochondrial and peroxisomal b-oxidation. The anti-estrogen agent tamoxifen has been used as an effective treatment for estrogen receptor-positive breast cancers for several years (1). However, tamoxifen treatment is associated with an increased risk of developing fatty liver (steatosis) (2-4), 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). It has been hypothesized that impaired fatty acid b-oxidation could be the cause of fatty liver after tamoxifen treatment (5, 6).The modified fatty acid tetradecylthioacetic acid (TTA) is a ligand for all peroxisome proliferator-activated receptors (PPARs) (7) and has shown promise in the prevention and treatment of common lipid disorders and insulin resistance (8). TTA increases both mitochondrial and peroxisomal b-oxidation in liver (9) and therefore may be a valuable tool for the treatment of fatty liver.In this study, female rats with 7,12-dimethylbenz[a]anthracene-induced mammary tumors were treated with tamoxifen, TTA, or a combination of tamoxifen and TTA (Tam1TTA) for 14 days after palpable tumors developed. We had two aims in this study: first, we wanted to elucidate the mechanism behind the accumulation of triacylglycerol in liver after tamoxifen treatment in this rat model; second, we wanted to investigate whether cotreatment with TTA could abolish this undesirable side effect of tamoxifen. To clarify the mechanisms involved, we measured the activities and gene expression of enzymes controlling the hep...

Study theeffect ofTamoxifenon Lipid profilein Male Albino Rats

“…In view of the results of the current study there is a significant increase in the level of serum Lipids when treated with TAM and elevation increased as the dose multiplied increased by the level of (30, 40, 50)mg/kg compared to the control group and this is consistent with [10][11][12][13].…”

Therapeutic Effect of Silybum marianum Plant Extract on Tamoxifen-Induced Fatty Liver in Rats

“…Since different plant extracts such as SME have antioxidant components, it might be that these compounds protect cells from damage caused by oxidative stress. On the other hand, the effect of SME on ameliorating of fatty liver is possibly due to inhibition of fatty acid synthesis or increasing of mitochondria and peroxisomal β-oxidation (18,19). Data of this study indicated that SME has therapeutic effects on tamoxifen induced fatty liver.…”

“…Tamoxifen is a toxic drug for liver tissue because of its higher affinity for hepatocytes compared with the other cells (17). Among various liver problems, NAFLD is the most common condition due to activation of fatty acid and triglyceride biosynthesis (18,19). In these patients, liver enzymes activities in serum and liver sonography are abnormal (4).…”

Histological Effects of Aqueous Extract of Moringa oleifera on the Liver Tissues of Wistar rats fed with High Fat Diet

“…These damages were as result of up-regulation of the key genes responsible for lipid biosynthesis in the liver and also the down-regulation of the gene for fatty acid oxidation 29,30 . The effect of Moringa oleifera in attenuating these damages is possibly due to upregulation of gene for fatty acid oxidation and or the down-regulation of hepatic biosynthetic genes 31,32 .…”