Correlation between thyroid hormone status and hepatic hyperplasia and hypertrophy caused by the peroxisome proliferator-activated receptor alpha agonist Wy-14,643.
Correlation between thyroid hormone status and hepatic hyperplasia and hypertrophy caused by the peroxisome proliferator-activated receptor alpha agonist Wy-14,643.
复制标题
DOI：
10.1186/1477-3163-3-9
复制
发表时间：
2004-05-24
影响因子：
--
通讯作者：
Badr M
中科院分区：
文献类型：
--
作者：
Wang C;Youssef J;Cunningham M;Badr M
代谢抑制剂鱼藤酮通过未知的机制抑制PPARα激动剂Wy-14,643引起的肝细胞增殖和肝癌的发生。由于缺乏甲状腺激素会降低肝肿大，而肝肿大是PPARα激动剂诱发肝癌的早期生物标志物，本研究旨在探讨鱼藤酮是否会干扰Wy-14,643改变动物甲状腺状态的能力。雄性B6C3F1小鼠在饲料中给予Wy-14643(100ppm)、鱼藤酮(600ppm)或两者的混合物，连续7天。细胞复制标志物溴脱氧尿嘧啶核苷(BrDU)通过皮下植入渗透压微量泵给药。实验结束后，采集血清，用固相放射免疫试剂盒检测皮质酮和甲状腺激素水平。此外，对肝组织标本进行BrDU免疫组织化学染色，以确定标记细胞的百分比。此外，细胞表面积由配备有平面Neoflar×40 0.75NA物镜的Zeiss Axioplan显微镜产生的图像确定。然后分析单个肝细胞周长的痕迹，并使用微量FL-4000计算细胞表面积。WY-14,643可引起大鼠肝脏重量、肝细胞BrDU标记指数(LI)和肝细胞表面积显著增加。在同时服用Wy-14,643和鱼藤酮的动物中，与单独服用Wy-14,643的小鼠相比，所有这些影响都明显不明显。单独使用鱼藤酮可降低肝脏重量、LI和表面积。对照组小鼠的自由甲状腺指数(FTI)为5.0±0.3，这是一个准确反映动物甲状腺状况的指数。在接触鱼藤酮的动物中，这些值下降到2.0±0.9，而在服用Wy-14,643的动物中，这些水平显著上升到7.7±0.9。同时服用鱼藤酮和Wy-14,643的小鼠FTI值降至3.4±0.8。动物甲状腺状况与肝细胞增殖率(R2=0.62)和肝细胞表面积(R2=0.83)密切相关。这些结果支持动物的甲状腺状态在PPARα诱导的肝细胞增殖和肝细胞增大中起作用的假说。已知这两个事件都有助于肝癌的表达，以响应PPARα的激活。
The metabolic inhibitor rotenone inhibits hepatocellular proliferation and the incidence of liver cancer resulting from exposure to the PPARα agonist Wy-14,643, via unknown mechanisms. Since the absence of thyroid hormones diminishes hepatomegaly, an early biomarker for the hepatocarcinogenicity induced by PPARα agonists, this study was undertaken to investigate whether rotenone might interference with the ability of Wy-14,643 to alter the animal thyroid status. Male B6C3F1 mice were given Wy-14,643 (100 ppm), rotenone (600 ppm) or a mixture of both, in the feed for 7 days. Bromodeoxyuridine (BrDU), marker of cell replication, was delivered through subcutaneously implanted osmotic mini-pumps. At the end of the experiment, sera were collected and corticosterone and thyroid hormone levels were measured by solid-phase radioimmunoassay kits. In addition, liver tissue samples were stained immunohistochemically for BrDU to determine percentages of labeled cells. Further, cell surface area was determined from images generated by a Zeiss Axioplan microscope equipped with a plan Neofluar ×40 0.75 na objective. Tracings of individual hepatocyte perimeters were then analyzed and cell-surface areas were calculated using MicroMeasure FL-4000. Wy-14,643 caused a significant increase in liver weights, hepatocyte BrDU labeling index (LI), and hepatocyte surface area. In animals which received both Wy-14,643 and rotenone simultaneously, all of these effects were significantly less pronounced compared with mice that received Wy-14,643 alone. Rotenone alone decreased liver weights, LI and surface area. The Free Thyroid Index (FTI), which provides an accurate reflection of the animal's thyroid status, was 5.0 ± 0.3 in control mice. In animals exposed to rotenone, these values decreased to 2.0 ± 0.9, but in animals which received Wy-14,643, levels increased significantly to 7.7 ± 0.9. FTI values decreased to 3.4 ± 0.8 in mice receiving both rotenone and Wy-14,643. A strong correlation was observed between the animal thyroid status and both, hepatocyte proliferation (r2 = 0.62), and hepatocyte surface area (r2 = 0.83). These results support the hypothesis that the thyroid status of the animal plays a role in PPARα-induced hepatocellular proliferation and liver cell enlargement. Both these events are known to contribute to the expression of liver cancer in response to the activation of PPARα.