Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor α
Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor α
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DOI：
10.1158/0008-5472.can-04-0322
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发表时间：
2004-06-01
期刊：
影响因子：
11.2
通讯作者：
Gonzalez, FJ
中科院分区：
文献类型：
--
作者：
Cheung, C;Akiyama, TE;Gonzalez, FJ
降脂贝特类药物作为核受体过氧化物酶体增殖物激活受体α（PPARalpha）的激动剂发挥作用。PPARalpha的持续激活导致大鼠和小鼠中肝肿瘤的发展。然而，人类似乎对贝特类药物诱导的过氧化物酶体增殖和肝癌的发展具有抗性。这种物种差异的分子基础尚不清楚。为了检查决定小鼠和人之间过氧化物酶体增殖物应答的物种差异的机制，产生了PPARalpha-人源化小鼠系，其中人PPARalpha在四环素应答调节系统的控制下在肝脏中表达。PPARalpha-人源化和野生型小鼠对用有效PPARalpha配体Wy-14643处理有反应，如通过诱导编码过氧化物酶体和线粒体脂肪酸代谢酶的基因以及导致的血清甘油三酯降低所揭示的。然而，令人惊讶的是，只有野生型小鼠而不是PPARa人源化小鼠表现出肝细胞增殖，如细胞周期控制基因的升高、5-溴-2 '-脱氧尿苷掺入肝细胞核的增加和肝肿大所揭示的。这些研究证实，在配体活化后，控制脂质代谢的PPARalpha介导的途径独立于控制细胞增殖途径的途径。这些发现还表明，人和小鼠PPARalpha之间的结构差异是贝特类药物治疗后观察到的肝癌发生的差异易感性的原因。PPARalpha人源化小鼠可作为药物开发和人类风险评估的模型，并确定过氧化物酶体增殖物的肝癌发生机制。
Lipid-lowering fibrate drugs function as agonists for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Sustained activation of PPARalpha leads to the development of liver tumors in rats and mice. However, humans appear to be resistant to the induction of peroxisome proliferation and the development of liver cancer by fibrate drugs. The molecular basis of this species difference is not known. To examine the mechanism determining species differences in peroxisome proliferator response between mice and humans, a PPARalpha-humanized mouse line was generated in which the human PPARalpha was expressed in liver under control of the tetracycline responsive regulatory system. The PPARalpha-humanized and wild-type mice responded to treatment with the potent PPARalpha ligand Wy-14643 as revealed by induction of genes encoding peroxisomal and mitochondrial fatty acid metabolizing enzymes and resultant decrease of serum triglycerides. However, surprisingly, only the wild-type mice and not the PPARalpha-humanized mice exhibited hepatocellular proliferation as revealed by elevation of cell cycle control genes, increased incorporation of 5-bromo-2'-deoxyuridine into hepatocyte nuclei, and hepatomegaly. These studies establish that following ligand activation, the PPARalpha-mediated pathways controlling lipid metabolism are independent from those controlling the cell proliferation pathways. These findings also suggest that structural differences between human and mouse PPARalpha are responsible for the differential susceptibility to the development of hepatocarcinomas observed after treatment with fibrates. The PPARalpha-humanized mice should serve as models for use in drug development and human risk assessment and to determine the mechanism of hepatocarcinogenesis of peroxisome proliferators.