Advances in understanding the regulation of apoptosis and mitosis by peroxisome-proliferator activated receptors in pre-clinical models: relevance for human health and disease.
Advances in understanding the regulation of apoptosis and mitosis by peroxisome-proliferator activated receptors in pre-clinical models: relevance for human health and disease.
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DOI：
10.1186/1476-5926-2-3
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发表时间：
2003-01-31
期刊：
影响因子：
--
通讯作者：
Roberts, Ruth
中科院分区：
文献类型：
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作者：
Boitier, Eric;Gautier, Jean-Charles;Roberts, Ruth
过氧化物酶体增殖物激活受体（PPARs）是一个涉及多种生物过程的相关受体家族。PPARs有3种主要的同种型，称为PPARα、PPARβ和PPARγ，每种都被组织成与配体结合、活化和DNA结合等功能相关的结构域。PPARs被配体激活，所述配体可以是内源性的，如脂肪酸或其衍生物，或者是合成的，如过氧化物酶体增殖剂、降血脂药物、抗炎或胰岛素增敏药物。一旦激活，PPARs与DNA结合并调节基因转录。不同的同种型在它们的表达模式上有所不同，从而为它们的功能提供线索。PPARα主要在肝脏中表达，而PPARγ在脂肪和一些巨噬细胞中表达。啮齿类动物肝脏中的PPARα活化与过氧化物酶体增殖、细胞凋亡抑制和细胞增殖诱导有关。激活PPARα调节细胞凋亡和增殖的机制尚不清楚，但可能涉及靶基因转录。类似地，在成纤维细胞向脂肪细胞的分化过程中，PPARγ参与细胞生长停滞的诱导。然而，它已经涉及结肠癌模型中细胞周期和细胞增殖的调节。PPARβ是APC/β-catenin/T细胞因子-4肿瘤抑制通路的下游靶基因，参与c-myc和cyclin D1等促生长基因的调控。PPARs表达的显著物种和组织差异使临床前数据外推至人类变得复杂。例如，在过去20年中，PPARα配体（如低脂血症贝特类药物）已广泛用于临床治疗心血管疾病，尽管观察到这些化合物是啮齿类动物致癌物，但临床使用贝特类药物的副作用很少。同样，临床前模型未预测到的不良临床反应与PPARγ配体有关。在这里，我们考虑在人类健康和疾病的背景下，在临床前有效性和安全性模型中看到的对PPAR配体的反应。
Peroxisome proliferator activated receptors (PPARs) are a family of related receptors implicated in a diverse array of biological processes. There are 3 main isotypes of PPARs known as PPARα, PPARβ and PPARγ and each is organized into domains associated with a function such as ligand binding, activation and DNA binding. PPARs are activated by ligands, which can be both endogenous such as fatty acids or their derivatives, or synthetic, such as peroxisome proliferators, hypolipidaemic drugs, anti-inflammatory or insulin-sensitizing drugs. Once activated, PPARs bind to DNA and regulate gene transcription. The different isotypes differ in their expression patterns, lending clues on their function. PPARα is expressed mainly in liver whereas PPARγ is expressed in fat and in some macrophages. Activation of PPARα in rodent liver is associated with peroxisome proliferation and with suppression of apoptosis and induction of cell proliferation. The mechanism by which activation of PPARα regulates apoptosis and proliferation is unclear but is likely to involve target gene transcription. Similarly, PPARγ is involved in the induction of cell growth arrest occurring during the differentiation process of fibroblasts to adipocytes. However, it has been implicated in the regulation of cell cycle and cell proliferation in colon cancer models. Less in known concerning PPARβ but it was identified as a downstream target gene for APC/β-catenin/T cell factor-4 tumor suppressor pathway, which is involved in the regulation of growth promoting genes such as c-myc and cyclin D1. Marked species and tissue differences in the expression of PPARs complicate the extrapolation of pre-clinical data to humans. For example, PPARα ligands such as the hypolipidaemic fibrates have been used extensively in the clinic over the past 20 years to treat cardiovascular disease and side effects of clinical fibrate use are rare, despite the observation that these compounds are rodent carcinogens. Similarly, adverse clinical responses have been seen with PPARγ ligands that were not predicted by pre-clinical models. Here, we consider the response to PPAR ligands seen in pre-clinical models of efficacy and safety in the context of human health and disease.