PPARs in the brain

The biology of peroxisome proliferator activated receptors (PPARs) in physiological and pathophysiological processes has been primarily studied in peripherial organs and tissues. Recently it became clear that PPARs play an important role for the pathogenesis of various disorders of the CNS. The finding that activation of PPARs, and in particular, the PPARgamma isoform, suppresses inflammation in peripherial macrophages and in models of human autoimmune disease, instigated the experimental evaluation of these salutary actions for several CNS disorders that have an inflammatory component. Activation of all PPAR isoforms, but especially of PPARgamma, has been found to be protective in murine in vitro and in vivo models of Multiple Sclerosis. The verification of these findings in human cells prompted the initiation of clinical studies evaluating PPARgamma activation in Multiple Sclerosis patients. Likewise, Alzheimer's disease has a prominent inflammatory component that arises in response to neurodegeneration and to extracellular deposition of beta-amyloid peptides. The fact that non steroidal anti-inflammatory drugs (NSAIDs) delay the onset and reduce the risk to develop Alzheimer's disease, while they also bind to and activate PPARgamma, led to the hypothesis that one dimension of NSAID protection in AD may be mediated by PPARgamma. Several lines of evidence from in vitro and in vivo studies have supported this hypothesis, using Alzheimer disease related transgenic cellular and animal models. The ability of PPAR agonists to elicit anti-amyloidogenic, anti-inflammatory and insulin sensitizing effects may account for the observed effects. A number of clinical trials employing PPAR agonists have yielded promising results and further trials are in preparation, which aim to delineate the exact mechanism of interaction. Animal models of other neurodegenerative diseases such as Parkinson's and Amyotrophic lateral sclerosis, both associated with a considerable degree of CNS inflammation, have been studied with a positive outcome. Yet it is not clear whether reduction of inflammation or additional mechanisms account for the observed neuroprotection. Less is known about the physiological role of PPARs for brain development, maintenance and function. Lesions from transgenic mouse models, however, provide evidence that PPARs may play pivotal roles for CNS development and function.     

PPARs信号通路与哺乳动物生殖

过氧化物酶体增殖因子活化受体(peroxisome proliferator-activated receptors,PPARs)在动物体内有着广泛的生物学作用,可调节脂类代谢、能量收支平衡以及细胞分裂分化等重要生理过程。已经发现,PPARs信号通路与糖尿病和癌症等许多重大疾病的发生有关。随着基因剔除技术的应用以及PPARs人工配体的开发利用,人们对PPARs的认识不断深入。现对PPARs通路在卵巢周期、黄体形成、胚胎着床、胎盘发育和雄性生殖等哺乳动物生殖系统中的表达、功能及作用机制进行综述。     

Preserved glucose tolerance in high-fat-fed C57BL/6 mice transplanted with PPARgamma-/-, PPARdelta-/-, PPARgammadelta-/-, or LXRalphabeta-/- bone marrow

Macrophage lipid metabolism and inflammatory responses are both regulated by the nuclear receptors PPAR and LXR. Emerging links between inflammation and metabolic disease progression suggest that PPAR and LXR signaling may alter macrophage function and thereby impact systemic metabolism. In this study, the function of macrophage PPAR and LXR in Th1-biased C57BL/6 mice was tested using a bone marrow transplantation approach with PPARgamma(-/-), PPARdelta(-/-), PPARgammadelta(-/-), and LXRalphabeta(-/-) cells. Despite their inhibitory effects on inflammatory gene expression, loss of PPARs or LXRs in macrophages did not exert major effects on obesity or glucose tolerance induced by a high-fat diet. Treatment with rosiglitazone effectively improved glucose tolerance in mice lacking macrophage PPARgamma, suggesting that cell types other than macrophages are the primary mediators of the anti-diabetic effects of PPARgamma agonists in our model system. C57BL/6 macrophages lacking PPARs or LXRs exhibited normal expression of most alternative activation gene markers, indicating that macrophage alternative activation is not absolutely dependent on these receptors in the C57BL/6 background under the conditions used here. These studies suggest that genetic background may be an important modifier of nuclear receptor effects in macrophages. Our results do not exclude a contribution of macrophage PPAR and LXR expression to systemic metabolism in certain contexts, but these factors do not appear to be dominant contributors to glucose tolerance in a high-fat-fed Th1-biased bone marrow transplant model.     

Molecular characterization of peroxisome proliferator-activated receptors (PPARs) and their gene expression in the differentiating adipocytes of red sea bream Pagrus major

To investigate the molecular mechanism of fish adipocyte differentiation, the three subtypes of PPAR genes (alpha, beta and gamma) were characterized in a marine teleost red sea bream (Pagrus major). The primary structures of red sea bream PPARs exhibited high degrees of similarities to their mammalian counterparts, and their gene expression was detected in various tissues including adipose tissue, heart and hepatopancreas. During the differentiation of primary cultured red sea bream adipocytes, three PPARs showed distinct expression patterns: The alpha subtype showed a transient increase and the beta gene expression tended to increase during adipocyte differentiation whereas the gene expression level of PPARgamma did not change. These results suggest that they play distinct roles in adipocyte differentiation in red sea bream. In the differentiating red sea bream adipocytes, mammalian PPAR agonists, 15-deoxy-Delta(12,14)-prostaglandin J(2), ciglitazone and fenofibrate did not show clear effects on the adipogenic gene expression. However, 2-bromopalmitate increased the PPARgamma and related adipogenic gene expression levels, suggesting the gamma subtype plays a central role in red sea bream adipocyte differentiation and in addition, fatty acid metabolites can be used as modulators of adipocyte function. Thus our study highlighted the roles of PPARs in fish adipocyte differentiation and provided information on the molecular mechanisms of fish adipocyte development.     

Docosahexaenoic acid suppresses the activity of peroxisome proliferator-activated receptors in a colon tumor cell line

Fatty acids are generally considered as agonists for peroxisome proliferator-activated receptors (PPARs). Fatty acids have been shown to bind to and transactivate PPARs; it is not known whether fatty acids act as generalized agonists for PPARs in different cell types, and thus, stimulate the expression of PPAR-regulated target genes. Here, we investigated the potency of unsaturated fatty acids on transactivation of PPRE, DNA-binding activity of PPARs, and the expression of a PPAR-regulated gene product, CD36. Docosahexaenoic acid (DHA) suppressed the basal and PPAR agonist-induced transactivation of PPRE, and DNA binding of PPARs in colon tumor cells (HCT116). The suppression of PPAR transactivation by DHA leads to reduced expression of CD36 in HCT116 cells and human monocytic cells (THP-1) as determined by promoter reporter gene assay and flow cytometric analysis. Our results demonstrate that DHA and other unsaturated fatty acids act as antagonists instead of agonists for transactivation of PPRE and PPAR-regulated gene expression in the cell lines tested. These results suggest that PPAR-mediated gene expression and cellular responses can be dynamically modulated by different types of dietary fatty acids consumed.     

Peroxisome proliferator activated receptor-gamma (PPAR-gamma) mediates the action of gamma linolenic acid in breast cancer cells

Gamma linolenic acid (GLA) is a polyunsaturated fatty acid, which induces cytotoxicity and regulates cell adhesion in cancer cells. The molecular mechanism of these actions is not clear. We have shown that GLA acts via peroxisome proliferator activated receptors (PPARs), by stimulating their phosphorylation and translocation to the nucleus. Removing PPAR gamma with antisense oligos abolished the effect of GLA on the expression of adhesion molecules and tumour suppressor genes, whereas removal of PPAR alpha had no effect. Tissues from patients with breast cancer showed a reduction of expression of both PPARs in cancer tissues, as compared with normal. Thus, PPAR gamma serves as the receptor for GLA in the regulation of gene expression in breast cancer cells.