Schoonjans K, Staels B, Auwerx J
U.325 INSERM, Départment d'Athérosclérose, Institut Pasteur de Lille, France.
J Lipid Res. 1996 May;37(5):907-25.
The three types of peroxisome proliferator-activated receptors (PPAR), termed alpha, delta (or beta), and gamma, belong to the nuclear receptor superfamily. Although peroxisome proliferators, including fibrates and fatty acids, activate the transcriptional activity of these receptors, only prostaglandin J2 derivatives have been identified as natural ligands of the PPAR gamma subtype that also binds thiazolidinedione antidiabetic agents with high affinity. PPARs heterodimerize with retinoic X receptor (RXR) and alter the transcription of target genes after binding to response elements or PPREs, consisting of a direct repeat of the nuclear receptor hexameric DNA recognition motif (PuGGTCA) spaced by 1 nucleotide (DR-1). Upon activation by fatty acids (FAs) and drugs that affect lipid metabolism, PPARs control the expression of genes implicated in intra- and extracellular lipid metabolism, most notably those involved in peroxisomal beta-oxidation. PPARs partially mediate the inductive effects of fibrates and fatty acids on high density lipoprotein (HDL) cholesterol levels by regulating the transcription of the major HDL apolipoproteins, apoA-I and apoA-II. The hypotriglyceridemic action of fibrates and certain fatty acids also involves PPAR and is constituted of: 1) increased hydrolysis of plasma triglycerides due to induction of LPL and reduction of apoC-III expression; 2) stimulation of cellular fatty acid uptake and conversion to acyl-CoA derivatives due to increased expression of genes for fatty acid transport protein and acyl-CoA synthetase; 3) increased peroxisomal and mitochondrial beta-oxidation; and 4) decreased synthesis of fatty acids and triglycerides and decreased production of very low density lipoprotein (VLDL). Hence, both enhanced catabolism of triglyceride-rich particles and reduced secretion of VLDL particles contribute to the hypolipidemic effect of fibrates and fatty acids. Finally, PPARs appear to be involved in differentiation processes because activation of PPAR gamma 2 triggers adipocyte differentiation and stimulates expression of several genes critical to adipogenesis. It is suggested that PPARs are key messengers responsible for the translation of nutritional and pharmacological stimuli into changes in gene expression and differentiation pathways.
过氧化物酶体增殖物激活受体（PPAR）有三种类型，分别称为α、δ（或β）和γ，属于核受体超家族。尽管包括贝特类药物和脂肪酸在内的过氧化物酶体增殖剂可激活这些受体的转录活性，但只有前列腺素J2衍生物被确定为PPARγ亚型的天然配体，该亚型也能与噻唑烷二酮类抗糖尿病药物高亲和力结合。PPAR与视黄酸X受体（RXR）形成异二聚体，并在与由核受体六聚体DNA识别基序（PuGGTCA）以1个核苷酸间隔的直接重复序列（DR-1）组成的反应元件或PPRE结合后改变靶基因的转录。在受到脂肪酸（FAs）和影响脂质代谢的药物激活后，PPAR控制参与细胞内和细胞外脂质代谢的基因的表达，最显著的是那些参与过氧化物酶体β氧化的基因。PPAR通过调节主要HDL载脂蛋白apoA-I和apoA-II的转录，部分介导贝特类药物和脂肪酸对高密度脂蛋白（HDL）胆固醇水平的诱导作用。贝特类药物和某些脂肪酸的降甘油三酯作用也涉及PPAR，其作用机制包括：1）由于LPL的诱导和apoC-III表达的降低，血浆甘油三酯的水解增加；2）由于脂肪酸转运蛋白和酰基辅酶A合成酶基因表达的增加，细胞脂肪酸摄取和转化为酰基辅酶A衍生物的刺激；3）过氧化物酶体和线粒体β氧化增加；4）脂肪酸和甘油三酯的合成减少以及极低密度脂蛋白（VLDL）的产生减少。因此，富含甘油三酯颗粒的分解代谢增强和VLDL颗粒分泌减少都有助于贝特类药物和脂肪酸的降血脂作用。最后，PPAR似乎参与分化过程，因为PPARγ2的激活触发脂肪细胞分化并刺激对脂肪生成至关重要的几个基因的表达。有人认为PPAR是负责将营养和药理刺激转化为基因表达和分化途径变化的关键信使。
