Xenobiotic Receptors

PPAR吗?-人源化小鼠系，其中人PPAR？（hPPAR?）通过放置hPPAR？多西环素控制的Tet-Off系统控制下的cDNA，并指定为hPPAR -TetOff。hPPAR吗?-TetOff和野生型小鼠对强效PPAR治疗有反应？通过诱导编码过氧化物酶体和线粒体脂质代谢酶的基因并降低血脂，揭示了配体Wy-14643。然而，只有野生型小鼠，而不是hPPAR？-TetOff小鼠表现出肝细胞增殖，肝细胞扩张，溴脱氧尿苷（BrdU）的掺入和许多细胞周期控制基因的诱导。此外，hPPAR？-TetOff对wy - 14643诱导的肝癌有耐药性；在20只小鼠中，经过1年的wy - 14643治疗后，只有一只小鼠表现出癌症，而野生型小鼠组的发病率为100%。这些发现表明贝特酸盐的物种特异性作用可能是由于mPPAR激活的基因谱的差异。与hPPAR ?贝特治疗后。这种基因表达的物种特异性调控将决定是贝特类药物还是其他PPAR？配体对肝脏有致癌作用。PPAR的作用？在结肠癌发生中。有相互矛盾的研究显示PPAR的影响？配体对结肠肿瘤生长的影响。如何分析PPAR的作用？PPAR？-/+和控制PPAR？+/+小鼠用结肠特异性致癌物偶氮氧甲烷处理。偶氮甲烷导致？-catenin水平与PPAR患者结肠癌发病率的关系？偶氮甲烷处理的-/+小鼠。然而，先前存在Apc损伤的小鼠，Apc是？-catenin，以对PPAR状态不敏感的方式发展肿瘤。这些数据表明PPAR？能压制吗？-catenin水平与结肠癌发生的关系，但仅在APC/？连环蛋白通路。这些发现揭示了PPAR的潜在重要用途。配体在结肠癌中的化学预防作用。PPAR的作用？在其他癌症中。确定PPAR？对其他类型癌症的影响，采用引发剂7,12-二甲基苯[a]蒽（DMBA）进行致癌生物测定，每周灌胃一次，持续6周，随访共25周。PPAR吗?-/+小鼠与PPAR？+/+窝友控制。PPAR吗?-/+小鼠对dmba诱导的总肿瘤、乳腺腺癌、卵巢颗粒细胞癌和小鼠皮肤乳头状瘤的易感性增加。他们还显示总体生存率下降，恶性肿瘤和转移发生率增加。这些结果首次证明了PPAR在体内的易感性增加。单倍体功能不全对dmba介导的癌变的影响，并提示PPAR？可作为皮肤、卵巢癌和乳腺癌的肿瘤调节剂。这些数据表明PPAR的有益作用。特异性配体在化学预防乳腺癌、卵巢癌和皮肤癌中的作用。

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.