PPARα:: Mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators
PPARα:: Mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators
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DOI：
10.1016/j.tox.2007.09.030
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发表时间：
2008-04-03
期刊：
影响因子：
4.5
通讯作者：
Shah, Yatrik A.
中科院分区：
文献类型：
--
作者：
Gonzalez, Frank J.;Shah, Yatrik A.
过氧化物酶体增殖剂化学品是典型的非遗传毒性致癌物。当长期给予大鼠和小鼠时，这些药剂会导致肝癌。过氧化物酶体增殖剂包括广泛使用的降脂和降胆固醇贝特类药物。与啮齿类动物的结果相反，没有证据表明贝特类与人类肝癌或任何其他肿瘤的风险升高相关，因此表明肝癌反应存在种属差异。过氧化物酶体增殖物的生物学效应是由过氧化物酶体增殖物激活受体（peroxisome proliferatoractivated receptor，PPAR）α介导的。Ppar alpha缺失小鼠对过氧化物酶体增殖剂的所有多效性作用具有抵抗力，包括细胞增殖和肝癌发生。肝细胞增殖的机制涉及通过PPAR下调microRNA let-7 c基因（X. Let-7 c通过使其mRNA不稳定来控制增殖性c-myc的水平。因此，在抑制let-7 c后，c-myc mRNA和蛋白质升高，导致肝细胞增殖增强。相比之下，通过降低血清甘油三酯和诱导编码脂肪酸代谢酶的基因来响应Wy-14，643的PPAR α人源化小鼠对过氧化物酶体增殖物诱导的细胞增殖和癌症具有抗性。这些小鼠没有表现出let-7 c基因表达下调，从而形成了对肝细胞致癌作用的抵抗力的基础。出版社：Elsevier爱尔兰Ltd.
Peroxisome proliferator chemicals are classic non-genotoxic carcinogens. These agents cause liver cancers when chronically administered to rats and mice. Peroxisome proliferators include the widely prescribed lipid and cholesterol lowering fibrate drugs. In contrast to the results in rodents, there is no evidence that fibrates are associated with elevated risk of liver cancer or any other neoplasms in humans thus indicating a species difference in the hepatocarcinogenic response. The biological effects of peroxisome proliferators are mediated by the peroxisome proliferatoractivated receptor (PPAR)alpha. Ppar alpha-null mice are resistant to all of the pleiotropic effects of peroxisome proliferators, including cell proliferation and hepatocarcinogenesis. The mechanism of hepatocellular proliferation involves downregulation of the microRNA let-7c gene by PPAR(X. Let-7c controls levels of proliferative c-myc by destabilizing its mRNA. Thus, upon suppression of let-7c, c-myc mRNA and protein are elevated resulting in enhanced hepatocellular proliferation. In contrast, PPAR alpha-humanized mice, that respond to Wy-14,643 by lower serum triglycerides and induction of genes encoding fatty acid metabolizing enzymes, are resistant to peroxisome proliferator-induced cell proliferation and cancer. These mice do not exhibit downregulation of let-7c gene expression thus forming the basis for the resistance to hepatocellular carcinogenesis. Published by Elsevier Ireland Ltd.