Role of peroxisome proliferator-activated receptor-α (PPARα) in bezafibrate-induced hepatocarcinogenesis and cholestasis
Role of peroxisome proliferator-activated receptor-α (PPARα) in bezafibrate-induced hepatocarcinogenesis and cholestasis
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DOI：
10.1093/carcin/bgh285
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发表时间：
2005-01-01
期刊：
影响因子：
4.7
通讯作者：
Peters, JM
中科院分区：
文献类型：
--
作者：
Hays, T;Rusyn, I;Peters, JM
啮齿类动物长期使用过氧化物酶体增殖剂通常会导致肝癌发生。过氧化物酶体增殖物激活受体-α（PPARalpha）需要介导PPARalpha靶基因表达的改变、抑制凋亡、增强复制性DNA合成、对DNA的氧化应激和由相对特异性PPARalpha激动剂Wy-14，643诱导的肝癌发生。有趣的是，在不存在PPARalpha表达的情况下，给予特异性较低的PPARalpha激动剂苯扎贝特导致适度诱导PPARalpha靶基因。在这些研究中，在野生型（+/+）和PPARalpha缺失（-/-）小鼠中检查了PPARalpha在调节长期喂食0.5%苯扎贝特诱导的肝癌发生中的作用。喂食苯扎贝特的（+/+）和（-/-）小鼠的平均肝脏重量显著高于对照组，但与相似处理的（+/+）小鼠相比，（-/-）小鼠的这种影响显著降低。在喂食苯扎贝特的（+/+）小鼠中发现编码细胞周期调节蛋白和DNA修复酶的mRNA水平升高，而在（-/-）小鼠中未发现这种效应。在喂食苯扎贝特1年的小鼠中，在（+/+）小鼠中发现了癌前病灶、腺瘤和肝细胞癌，而在1只（-/-）小鼠中仅发现了单个显微镜下腺瘤。在Sv/129和C57 BL/6 N小鼠品系中均观察到这种效应，尽管在后者品系中仅观察到癌前病灶。有趣的是，在100%的苯扎贝特喂养（-/-）小鼠中观察到肝胆汁淤积，这伴随着编码胆盐输出泵的mRNA的肝脏表达显著升高和编码细胞色素P450 7A 1的mRNA的表达降低，与胆汁酸受体法尼醇X受体的激活增强一致。这些研究的结果表明，PPARalpha是介导苯扎贝特诱导的肝癌发生所必需的，并且PPARalpha可防止潜在的胆汁淤积。
Prolonged administration of peroxisome proliferators to rodents typically leads to hepatocarcinogenesis. Peroxisome proliferator-activated receptor-alpha (PPARalpha) is required to mediate alterations in PPARalpha target gene expression, repress apoptosis, enhance replicative DNA synthesis, oxidative stress to DNA and hepatocarcinogenesis induced by the relatively specific PPARalpha agonist, Wy-14,643. Interestingly, administration of the less specific PPARalpha agonist, bezafibrate, leads to a modest induction of PPARalpha target genes in the absence of PPARalpha expression. In these studies, the role of PPARalpha in modulating hepatocarcinogenesis induced by long-term feeding of 0.5% bezafibrate was examined in wild-type (+/+) and PPARalpha-null (-/-) mice. The average liver weight was significantly higher in (+/+) and (-/-) mice fed bezafibrate than controls, but this effect was considerably less in (-/-) mice as compared with similarly treated (+/+) mice. Increased levels of mRNA encoding cell cycle regulatory proteins and DNA repair enzymes were found in (+/+) mice fed bezafibrate, and this effect was not found in (-/-) mice. In mice fed bezafibrate for 1 year, preneoplastic foci, adenomas and a hepatocellular carcinoma were found in (+/+) mice, while only a single microscopic adenoma was found in one (-/-) mouse. This effect was observed in both Sv/129 and C57BL/6N strains of mice, although only preneoplastic foci were observed in the latter strain. Interestingly, hepatic cholestasis was observed in 100% of the bezafibrate-fed (-/-) mice, and this was accompanied by significantly elevated hepatic expression of mRNA encoding bile salt export pump and lower expression of mRNA encoding cytochrome P450 7A1, consistent with enhanced activation of the bile acid receptor, farnesoid X receptor. Results from these studies demonstrate that the PPARalpha is required to mediate hepatocarcinogenesis induced by bezafibrate, and that PPARalpha protects against potential cholestasis.