Xenobiotic Receptors

建立了人PPAR？人源化小鼠系，人PPAR？(hPPAR？)通过放置hPPAR在肝脏中表达？多西环素控制的Tet-Off系统控制下的c DNA，并命名为hPPAR？HPPAR？-TetOff和野生型小鼠对强大的PPAR？配体Wy-14643，通过诱导编码过氧化物体和线粒体脂肪代谢酶的基因以及降低血脂来揭示。然而，只有野生型小鼠而不是hPPAR？-TetOff小鼠表现出肝细胞的增殖，表现为肝脏肿大，掺入溴脱氧尿苷(BrdU)，并诱导了许多细胞周期控制基因。此外，hPPAR？-TetOff对Wy-14,643诱导的肝癌具有抵抗力；在20只小鼠中，只有一只在Wy-14,643治疗一年后出现癌症，而野生型小鼠组的发病率为100%。这些发现表明，贝特类的物种特异性效应可能是由于mPPAR？激活的基因图谱的差异。与hPPAR相比？在贝特治疗后。基因表达的这种特定物种的调节将决定贝特类药物或其他PPAR？配体对肝脏有致癌作用。PPAR的作用是什么？在结肠癌发生中的作用。有相互矛盾的研究表明PPAR的影响？配体对结肠癌生长的影响。分析PPAR的作用？在结肠癌发生过程中，PPAR？-/+组和对照组PPAR？+/+组小鼠用结肠特异性致癌物质偶氮氧甲烷进行治疗。在接受偶氮甲烷治疗的PPAR？-/+小鼠中，偶氮甲烷导致β-连环蛋白水平的增加和结肠癌的更高发病率。然而，预先存在对β-连环蛋白调节因子APC的损伤的小鼠，会以一种对PPAR？状态不敏感的方式发生肿瘤。这些数据表明，PPAR？可以抑制β-连环蛋白水平和结肠癌的发生，但只能在损伤APC/？-连环蛋白途径之前。这些发现揭示了PPAR的潜在重要用途？配体作为结肠癌的化学预防药物。PPAR？在其他癌症中。以确定PPAR是否？以7，12-二甲基苯并[a]菲(DMBA)为引发剂，经口灌胃给药，每周1次，连续6周，共25周。将PPAR？-/+小鼠与PPAR？+/+仔鼠进行比较。PPAR？-/+小鼠对DMBA诱发的总肿瘤、乳腺癌、卵巢颗粒细胞癌和小鼠皮肤乳头状瘤的易感性增加。他们还显示，总体存活率下降，恶性肿瘤和转移率上升。这些结果首次证明PPAR？在体内的敏感性增加。对DMBA介导的致癌作用的单倍性不足，提示PPAR？可作为皮肤癌、卵巢癌和乳腺癌的肿瘤修饰物。这些数据表明，PPAR？特异性配体在化学预防乳腺癌、卵巢癌和皮肤癌方面发挥了有益的作用。

A PPAR?-humanized mouse line was generated in which the human PPAR? (hPPAR?) was expressed in the liver by placing the hPPAR? cDNA under control of the Tet-Off system of doxycyclin control and designated hPPAR?-TetOff. The hPPAR?-TetOff and wild-type mice responded to treatment with the potent PPAR? ligand Wy-14643 as revealed by the induction of genes encoding peroxisomal and mitochondrial lipid-metabolizing enzymes and lowering of serum lipids. However, only the wild-type mice and not the hPPAR?-TetOff mice exhibited hepatocellular proliferation as revealed by hepatomegally, incorporation of bromdeoxyuridine (BrdU) and induction of numerous cell cycle control genes. In addition, the hPPAR?-TetOff were resistant to Wy-14,643-induced hepatocarcinogenesis; from 20 mice, only one exhibited a carcinoma after 1 year of Wy-14,643 treatment in contrast to a 100% incidence in the wild-type mouse group. These findings suggest that the species-specific effects of fibrates are likely due to differences in the profile of genes activated by mPPAR? versus hPPAR? following fibrate treatment. This species-specific regulation of gene expression will dictate whether a fibrate drug or other PPAR? ligand exhibits carcinogenic effects on the liver. Role of PPAR? in colon carcinogenesis. There are conflicting studies showing the effects of PPAR? ligands on growth of colon tumors. To analyze the role of PPAR? in colon carcinogenesis, PPAR?-/+ and control PPAR?+/+ mice were treated with the colon-specific carcinogen azoxymethane. Azoxymethane causes an increase in ?-catenin levels and a greater incidence of colon cancer in PPAR?-/+ mice treated with azoxymethane. However, mice with preexisting damage to Apc, a regulator of ?-catenin, develop tumors in a manner insensitive to the status of PPAR?. These data show that PPAR? can suppress ?-catenin levels and colon carcinogenesis but only before damage to the APC/?-catenin pathway. These findings reveal a potentially important use for PPAR? ligands as chemopreventative agents in colon cancer.Role of PPAR? in other cancers. To determine whether PPAR? affects other types of cancers a carcinogenesis bioassay was performed using the initiator 7,12-dimethylbenz[a]anthracene (DMBA) administered by oral gavage once a week for 6 weeks and followed for a total of 25 weeks. PPAR?-/+ mice were compared with PPAR?+/+ littermate controls. PPAR?-/+ mice exhibited increased susceptibility to DMBA-induced total tumors, mammary adenocarcinomas, ovarian granulosa cell carcinomas and mouse skin papillomas. They also showed a decreased overall survival and an increase in malignant tumors and metastatic incidence. These results are the first to demonstrate an increased susceptibility in vivo of PPAR? haploinsufficiency to DMBA-mediated carcinogenesis and suggest that PPAR? may act as a tumor modifier of skin, ovarian and breast cancers. These data suggest a beneficial role for PPAR?-specific ligands in the chemoprevention of mammary, ovarian and skin carcinogenesis.