Peroxisome proliferators and peroxisome proliferator activated receptors (PPARs) as regulators of lipid metabolism
Peroxisome proliferators and peroxisome proliferator activated receptors (PPARs) as regulators of lipid metabolism
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DOI：
10.1016/s0300-9084(97)81496-4
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发表时间：
1997-02-01
期刊：
影响因子：
3.9
通讯作者：
Vamecq, J
中科院分区：
文献类型：
--
作者：
Latruffe, N;Vamecq, J
哺乳动物细胞中的过氧化物酶体增殖（PP）在30年前首次被描述，是现代研究的一个引人入胜的领域。通过在细胞生物学、生物化学和遗传学方面开辟新领域的基本进展，对其认识取得了重大进展。在PP首次报道十年后，发现了一种新的代谢途径（过氧化物酶体β -氧化）及其由过氧化物酶体增殖体诱导的能力。最近，一种新的核受体，过氧化物酶体增殖激活受体（PPAR），已经被描述。首个PPAR是在1990年发现的。从那时起，许多其他ppar已经被描述。这类原始的核受体属于类固醇受体超家族。随着细胞信号转导途径的激活，ppar的发生首次为PP的触发机制提供了连贯的解释。然而，尽管许多化合物或代谢物能够激活PPAR，但迄今为止，这些受体的天然直接配体尚未被明确鉴定，但15-deoxy-12,14-前列腺素J2是PPAR γ 2的配体，而白三烯LTB4结合PPAR α。在这个阶段，不能排除一些孤儿ppar（即没有已知配体的受体）的假设。尽管存在这些相对限制性的方面，但ppar激活导致PP的机制已经很清楚；此外，可以提出一些连贯的假设，其中涉及受体磷酸化或热休克蛋白（即HSP 72）的情况可以解释ppar如何被激活。本文综述了近年来PPAR的研究进展，介绍了目前公认的PPAR家族成员，它们的特征、功能、调控和激活机制，以及它们在脂质代谢调控中的作用，如控制β -氧化、生酮、脂肪酸合成和脂蛋白代谢。作为引言部分，简要回顾了从哺乳动物首次发现PPAR到首次报道PPAR之间的主要事件。另一部分致力于目前关于PPAR激活和PP诱导机制的假设。而不是详尽的介绍细胞改变伴随PP诱导，脂质代谢的动态概述提供。通过评估这一细胞器增殖过程的生物学意义，读者将得出结论，ppar的发现以及通过过氧化物酶体增殖反应元件（PPRE）激活的相关基因，使PP诱导成为脂质代谢中发生的控制的最具说明意义的例子之一。
Peroxisome proliferation (PP) in mammalian cells, first described 30 years ago, represents a fascinating field of modern research. Major improvements made in its understanding were obtained through basic advances that have opened up new areas in cell biology, biochemistry and genetics. A decade after the first report on PP, a new metabolic pathway (peroxisomal beta-oxidation) and its inducibility by peroxisome proliferators were discovered. More recently, a new type of nuclear receptor, the peroxisome proliferator-activated receptor (PPAR), has been described. The first PPAR was discovered in 1990. Since then, many other PPARs have been characterized. This original class of nuclear receptors belongs to the superfamily of steroid receptors. With activation of cell signal transduction pathways, the occurrence of PPARs provides, for the first time, a coherent explanation of mechanisms by which PP is triggered. Nevertheless, although many compounds or metabolites are capable of activating PPARs, the natural direct ligands of these receptors have not been, up to now, clearly identified, with, however, the exception of 15-deoxy-12,14-prostaglandin J2 which is the ligand of PPAR gamma 2 while leukotrien LTB4 binds PPAR alpha. At this stage, the hypothesis of some orphan PPARs (ie receptors without known ligand) can not be ruled out. Despite these relatively restrictive aspects, the mechanisms by which activation of PPARs leads to PP become clear; also, coherent hypotheses among which a scenario involving receptor phosphorylation or a heat shock protein (ie HSP 72) can be proposed to explain how PPARs would be activated. The aim of this note is to review recent developments on PPARs, to present members up to now recognized to belong to the PPAR family, their characterization, functions, regulation and mechanisms of activation as well as their involvement in lipid metabolism regulation such as control of beta-oxidation, ketogenesis, fatty acid synthesis and lipoprotein metabolism. As an introducing section, a brief review of the major events between the first report of PP in mammals and the discovery of the first PPAR is given. Another section is devoted to current hypotheses on mechanisms responsible for PPAR activation and PP induction. Rather than an exhaustive presentation of cellular alterations accompanying PP induction, a dynamic overview of the lipid metabolism is provided. By assessing the biological significance of this organellar proliferative process, the reader will be led to conclude that the discovery of PPARs and related gene activation through peroxisome proliferator responsive element (PPRE) makes PP induction one of the most illustrative examples of control that occurs in lipid metabolism.