Peroxisome proliferator-activated receptors and the regulation of mammalian lipid metabolism.
Peroxisome proliferator-activated receptors and the regulation of mammalian lipid metabolism.
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DOI：
10.1042/bst0301086
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发表时间：
2001-12
影响因子：
3.9
通讯作者：
S. Smith
中科院分区：
文献类型：
--
作者：
S. Smith
过氧化物酶体增殖物激活受体（PPARs）是配体激活的核转录因子超家族的成员。在哺乳动物中已经描述了三种PPAR亚型，PPARalpha、PPARdelta（PPARbeta）和PPARgamma。PPARs的组织分布是异质的：PPARalpha在肝脏和骨骼肌中高度表达，PPARgamma优先在脂肪组织中表达，PPARdelta在大多数细胞类型中以相对丰度表达。与大多数受体不同，PPARs显示出低配体特异性，被许多长链饱和和不饱和脂肪酸或类花生酸激活。PPARs作为与类维生素A X受体的异二聚体复合物具有转录活性，并与靶基因调控区的特异性识别序列结合。许多PPAR调节基因编码调节脂肪酸氧化和储存的蛋白质。PPARs的生物学功能的阐明已经通过开发PPAR-null小鼠和鉴定携带PPARs突变的人类，以及发现选择性激活单个PPARs亚型的合成小分子配体而得到帮助。使用这些遗传学和药理学方法，已经表明PPARalpha主要调节脂肪酸氧化途径，而PPARgamma修饰脂肪组织中的脂肪酸合成和储存。噻唑烷二酮PPARgamma激活剂通过降低全身脂肪酸利用率来调节葡萄糖代谢，目前临床上用于治疗II型糖尿病。总之，PPARs在面对膳食脂肪摄入和能量消耗的波动时平衡脂肪酸氧化和储存的机制中发挥核心作用。
Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of ligand-activated nuclear transcription factors. Three PPAR subtypes, PPARalpha, PPARdelta (PPARbeta) and PPARgamma, have been described in mammals. The tissue distribution of PPARs is heterogeneous: PPARalpha is highly expressed in liver and skeletal muscle, PPARgamma is preferentially expressed in adipose tissues, and PPARdelta is expressed in most cell types with relative abundance. Unlike most receptors, PPARs show low ligand specificity, being activated by many long-chain saturated and unsaturated fatty acids, or by eicosanoids. PPARs are transcriptionally active as heterodimeric complexes with the retinoid X receptor and bind to specific recognition sequences in the regulatory region of target genes. Many PPAR-regulated genes encode proteins that regulate fatty acid oxidation and storage. Elucidation of the biological functions of PPARs has been aided by the development of PPAR-null mice and the identification of humans bearing PPAR mutations, together with the discovery of synthetic small-molecule ligands that selectively activate individual PPAR subtypes. Using these genetic and pharmacological approaches, it has been shown that PPARalpha predominantly regulates pathways of fatty acid oxidation, whereas PPARgamma modifies fatty acid synthesis and storage in adipose tissues. By reducing systemic fatty acid availability, thiazolidinedione PPARgamma activators regulate glucose metabolism and are now used clinically in the treatment of Type II diabetes. In summary, PPARs play a central role in the mechanisms that balance fatty acid oxidation and storage in the face of fluctuations of dietary fat intake and energy expenditure.