Peroxisome proliferator-activated receptors in the cardiovascular system

Peroxisome proliferator-activated receptor (PPAR)s are a family of three nuclear hormone receptors, PPARalpha, -delta, and -gamma, which are members of the steriod receptor superfamily. The first member of the family (PPARalpha) was originally discovered as the mediator by which a number of xenobiotic drugs cause peroxisome proliferation in the liver. Defined functions for all these receptors, until recently, mainly concerned their ability to regulate energy balance, with PPARalpha being involved in beta-oxidation pathways, and PPARgamma in the differentiation of adipocytes. Little is known about the functions of PPARdelta, though it is the most ubiquitously expressed. Since their discovery, PPARs have been shown to be expressed in monocytes/macrophages, the heart, vascular smooth muscle cells, endothelial cells, and in atherosclerotic lesions. Furthermore, PPARs can be activated by a vast number of compounds including synthetic drugs, of the clofibrate, and anti-diabetic thiazoldinedione classes, polyunsaturated fatty acids, and a number of eicosanoids, including prostaglandins, lipoxygenase products, and oxidized low density lipoprotein. This review will aim to introduce the field of PPAR nuclear hormone receptors, and discuss the discovery and actions of PPARs in the cardiovascular system, as well as the source of potential ligands.     

Peroxisome proliferator-activated receptors (PPARS) and carcinogenesis.

Peroxisome proliferators (PPs) are an important group of chemicals that include certain hypolipidemic drugs, plasticizers and pollutants. Many of these agents are known rodent liver tumor promoters and debate exists as to whether humans are at increased cancer risk following exposure to PPs. Research over the last decade has focused on determining the biochemical and molecular mechanisms by which peroxisome proliferators exert their effects, in the hope that this controversy will be settled. PPs regulate gene expression via a steroid hormone receptor, the peroxisome proliferator-activated receptor (PPAR). At least three subtypes of PPAR (alpha, beta and gamma) have been cloned from several species, including humans. These receptors have been implicated in tumor promotion, cellular differentiation, and apoptosis. In the present article, the current understanding of how PPARs are involved in tumorigenesis, and what this may mean to human risk assessment, will be discussed.     

Peroxisome proliferator-activated receptor ligands in atherosclerosis

In this review, the effect of peroxisome proliferator-activated receptor (PPAR) ligands on atherosclerosis is examined. The PPAR-γ agonist thiazolidinediones are currently indicated for the management of Type 2 diabetes mellitus, and the PPAR-α agonist fibrates are used in dyslipidaemia. Here their mechanism of action and the pre-clinical and clinical evidence for the use of these medications for the prevention and treatment of atherosclerotic disease is explored. In addition, the role of PPAR-δ and the possibilities for the role of dual-binding agonists are examined.     

Peroxisome proliferator-activated receptor ligands in atherosclerosis

In this review, the effect of peroxisome proliferator-activated receptor (PPAR) ligands on atherosclerosis is examined. The PPAR-gamma agonist thiazolidinediones are currently indicated for the management of Type 2 diabetes mellitus, and the PPAR-alpha agonist fibrates are used in dyslipidaemia. Here their mechanism of action and the pre-clinical and clinical evidence for the use of these medications for the prevention and treatment of atherosclerotic disease is explored. In addition, the role of PPAR-delta and the possibilities for the role of dual-binding agonists are examined.     

Crosstalk of vascular 5-HT1 receptors with other receptors: clinical implications

Blood vessels may either constrict or dilate in response to 5-HT, the response being dependent on the species, the vascular bed studied and the condition (healthy or diseased) of the subject studied. Vasoconstriction may be mediated by 5-HT_2A, but, in a variable proportion, also by 5-HT_1B receptors. The expression and function of 5-HT_1B receptors is likely to be increased in disease states such as hypertension, cerebrovascular disease and variant angina pectoris. Contractile responses mediated by 5-HT_1B receptors may be increased in blood vessels with damaged endothelium, but may also be augmented in the presence of low concentrations of other vasoconstrictors such as thromboxane A₂, endothelin-1, prostaglandin F_2α, angiotensin II, histamine, noradrenaline, phenylephrine or KCl. Such an augmentation, however, is not a generalized phenomenon, since it does not occur in all vascular beds and is not always induced by all substances mentioned above. Whereas the augmentation seems to depend on increased levels of the second messengers involved, the exact mechanism is not yet completely clear. The augmentation of 5-HT_1B receptor-mediated contractions may be of relevance in pathophysiological conditions such as variant angina and preeclampsia, where the development of 5-HT_1B receptors seems to be expedited. Further, augmentation of 5-HT_1B receptor-mediated contractions may be an important determinant in the case of chest symptoms experienced as a side effect of antimigraine drugs.     

Peroxisome proliferator-activated receptors: mediators of phthalate ester-induced effects in the male reproductive tract?

Many phthalate ester plasticizers are classified as peroxisome proliferators (PP), a large group of industrial and pharmaceutical chemicals. Like PP, exposure to some phthalates increases hepatocyte peroxisome and cellular proliferation, as well as the incidence of hepatocellular adenomas in mice and rats. Most effects of PP are mediated by three nuclear receptors called peroxisome proliferator-activated receptors (PPARalpha,beta,gamma). An obligate role for PPARalpha in PP-induced events leading to liver cancer is well-established. Exposure of rats in utero or in the neonate to a subset of phthalate esters causes profound, sometimes irreversible malformations in the male reproductive tract. We review here the data that supports or discounts roles for PPARs in phthalate-induced testis toxicity including (1) toxic effects of phthalates on the male reproductive tract, (2) expression of PPARs in the testis, (3) activation of PPARs by phthalates, (4) role of PPARalpha in testis toxicity, (5) gene targets of phthalates involved in steroid biosynthesis and catabolism, and (6) interactions between PPARs and other nuclear receptors that play roles in testis development and homeostasis. Critical research needs are identified that will help determine the significance of PPARs in phthalate-induced effects in the rat male reproductive tract and the relevance of toxicity to humans.     

过氧化酶体增殖物激活受体与非酒精性脂肪性肝病

<正>脂肪肝是由多种疾病和病因引起的肝脏脂肪性变。所谓脂肪性变是指细胞浆内出现的脂肪滴超过了生理范围或者正常不出现脂滴的细胞中出现了脂滴。根据是否有过量酒精摄入,可将脂肪性肝炎分为酒精性脂肪性肝炎(ASH)和非酒精性脂肪性肝炎(NASH)。非酒精性脂肪性肝病(Non—