The impact of fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-&#x3b1;) agonist, on the risk of thrombolysis-induced hemorrhage during the acute phase of stroke in a rat model of stroke was studied. One-hour middle cerebral artery occlusion followed by thrombolysis with tissue plasminogen activator was made in rats receiving either fenofibrate or vehicle for 72&#x2009;h after stroke. Evaluation of infarct, hemorrhage, middle cerebral artery vasoreactivity, and immunochemistry (CD11b for microglial activation, myeloperoxidase, and ICAM-1 for neutrophil infiltration) was performed. The PPAR-alpha agonist significantly reduced the risk of hemorrhage after thrombolysis in parallel with a decrease in the infarct volume and in the stroke-induced vascular endothelial dysfunction. These effects are concomitant with a reduction in microglial activation and neutrophil infiltration in infarct area. Our results strengthen the idea that using drugs such as fenofibrate, with pleiotropic properties due to PPAR-alpha agonism, may be of value to reduce thrombolysis-induced hemorrhage during acute stroke.

Sophie Gautier

Thavarak Ouk

Maud P&#xe9;trault

Olivier P&#xe9;trault

Vincent B&#xe9;r&#xe9;zowski

R&#xe9;gis Bordet

PPAR-Alpha Agonist Used at the Acute Phase of Experimental Ischemic Stroke Reduces Occurrence of Thrombolysis-Induced Hemorrhage in Rats

Thiazolidinediones (TZDs) are one of the major classes of antidiabetic drugs that are used widely. TZDs improve insulin resistance by activating peroxisome proliferator-activated receptor gamma (PPAR&#x3b3;) and ameliorate diabetic and other nephropathies, at least, in experimental animals. However, TZDs have side effects, such as edema, congestive heart failure, and bone fracture, and may increase bladder cancer risk. Edema and heart failure, which both probably originate from renal sodium retention, are of great importance because these side effects make it difficult to continue the use of TZDs. However, the pathogenesis of edema remains a matter of controversy. Initially, upregulation of the epithelial sodium channel (ENaC) in the collecting ducts by TZDs was thought to be the primary cause of edema. However, the results of other studies do not support this view. Recent data suggest the involvement of transporters in the proximal tubule, such as sodium-bicarbonate cotransporter and sodium-proton exchanger. Other studies have suggested that sodium-potassium-chloride cotransporter 2 in the thick ascending limb of Henle and aquaporins are also possible targets for TZDs. This paper will discuss the recent advances in the pathogenesis of TZD-induced sodium reabsorption in the renal tubules and edema.

Shoko Horita

Motonobu Nakamura

Nobuhiko Satoh

Masashi Suzuki

George Seki

Thiazolidinediones and Edema: Recent Advances in the Pathogenesis of Thiazolidinediones-Induced Renal Sodium Retention

Fibrosis is recognized as an important feature of many chronic diseases, such as systemic sclerosis (SSc), an autoimmune disease of unknown etiology, characterized by immune dysregulation and vascular injury, followed by progressive fibrosis affecting the skin and multiple internal organs. SSc has a poor prognosis because no therapy has been shown to reverse or arrest the progression of fibrosis, representing a major unmet medical need. Recently, antifibrotic effects of PPAR&#x3B3; ligands have been studied in vitro and in vivo and some theories have emerged leading to new insights. Aberrant PPAR&#x3B3; function seems to be implicated in pathological fibrosis in the skin and lungs. This antifibrotic effect is mainly related to the inhibition of TGF-&#x3b2;/Smad signal transduction but other pathways can be involved. This review focused on recent studies that identified PPAR&#x3B3; as an important novel pathway with critical roles in regulating connective tissue homeostasis, with emphasis on skin and lung fibrosis and its role on systemic sclerosis.

Andr&#xe9;a Tavares Dantas

Michelly Cristiny Pereira

Moacyr Jesus Barreto de Melo Rego

Laurindo Ferreira da Rocha

Ivan da Rocha Pitta

Cl&#xe1;udia Diniz Lopes Marques

Angela Luzia Branco Pinto Duarte

Maira Galdino da Rocha Pitta

The Role of PPAR Gamma in Systemic Sclerosis

Nitrooleic acid (OA-NO2) is endogenous ligands for peroxisome proliferator-activated receptors. The present study was aimed at investigating the beneficial effects of OA-NO2 on the lipid metabolism and liver steatosis in deoxycorticosterone acetate- (DOCA-) salt induced hypertensive mice model. Male C57BL/6 mice were divided to receive DOCA-salt plus OA-NO2 or DOCA-salt plus vehicle and another group received neither DOCA-salt nor OA-NO2 (control group). After 3-week treatment with DOCA-salt plus 1&#x25; sodium chloride in drinking fluid, the hypertension was noted; however, OA-NO2 had no effect on the hypertension. In DOCA-salt treated mice, the plasma triglyceride and total cholesterol levels were significantly increased compared to control mice, and pretreatment with OA-NO2 significantly reduced these parameters. Further, the histopathology of liver exhibited more lipid distribution together with more serious micro- and macrovesicular steatosis after DOCA-salt treatment and that was consistent with liver tissue triglyceride and nonesterified fatty acids (NEFA) content. The mice pretreated with OA-NO2 showed reduced liver damage accompanied with low liver lipid content. Moreover, the liver TBARS, together with the expressions of gp91phox and p47phox, were parallelly decreased. These findings indicated that OA-NO2 had the protective effect on liver injury against DOCA-salt administration and the beneficial effect could be attributed to its antihyperlipidemic activities.

Haiping Wang

Jing Sun

Zhanjun Jia

Tianxin Yang

Liang Xu

Bing Zhao

Kezhou Yu

Rong Wang

Nitrooleic Acid Attenuates Lipid Metabolic Disorders and Liver Steatosis in DOCA-Salt Hypertensive Mice

The mechanism by which Huaier, a Chinese traditional medicine, protects podocytes remains unclear. We designed the present study to examine whether mitochondrial function restored by PGC-1<svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" style="vertical-align:-0.2129903pt" id="M2" height="6.42315pt" version="1.1" viewBox="-0.0498162 -6.21016 7.82384 6.42315" width="7.82384pt"><g transform="matrix(.0135,0,0,-0.0135,0,0)"><path id="g113-223" d="M545 106L524 126C493 85 467 65 455 65C438 65 427 113 405 238C448 295 498 362 543 439L533 448L478 435C453 386 423 331 398 295H395C370 404 347 448 282 448C169 448 23 309 23 153C23 54 65 -12 128 -12C203 -12 283 70 339 155H341C360 29 380 -12 411 -12C444 -12 491 11 545 106ZM333 204C265 95 210 54 169 54C137 54 113 96 113 171C113 302 191 405 252 405C301 405 318 306 333 204Z"/></g></svg> serves as the major target of Huaier cream in protecting ADR nephropathy. After ADR administration, the podocytes exhibited remarkable cell injury and mitochondrial dysfunction. Additionally, ADR also reduced PGC-1<svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" style="vertical-align:-0.2129903pt" id="M3" height="6.42315pt" version="1.1" viewBox="-0.0498162 -6.21016 7.82384 6.42315" width="7.82384pt"><g transform="matrix(.0135,0,0,-0.0135,0,0)"><use xlink:href="#g113-223"/></g></svg> both in vivo and in vitro. Following the Huaier treatment, the notable downregulation of PGC-1<svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" style="vertical-align:-0.2129903pt" id="M4" height="6.42315pt" version="1.1" viewBox="-0.0498162 -6.21016 7.82384 6.42315" width="7.82384pt"><g transform="matrix(.0135,0,0,-0.0135,0,0)"><use xlink:href="#g113-223"/></g></svg> and its downstream molecule mitochondrial transcription factor A (TFAM) were almost entirely blocked. Correspondingly, Huaier markedly ameliorated ADR-induced podocyte injury and mitochondrial dysfunction in both rat kidneys and incubated cells as it inhibited the decrease of nephrin and podocin expression, mtDNA copy number, MMP, and ATP content. Transmission electron microscopy result also showed that Huaier protected mitochondria against ADR-induced severe mitophagy and abnormal changes of ultrastructural morphology. In conclusion, Huaier can protect podocytes against ADR-induced cytotoxicity possibly by reversing the dysfunction of mitochondria via PGC-1<svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" style="vertical-align:-0.2129903pt" id="M5" height="6.42315pt" version="1.1" viewBox="-0.0498162 -6.21016 7.82384 6.42315" width="7.82384pt"><g transform="matrix(.0135,0,0,-0.0135,0,0)"><use xlink:href="#g113-223"/></g></svg> overexpression, which may be a novel therapeutic drug target in glomerular diseases.

Ruochen Che

Chunhua Zhu

Guixia Ding

Min Zhao

Mi Bai

Aihua Zhang

Songming Huang

Huaier Cream Protects against Adriamycin-Induced Nephropathy by Restoring Mitochondrial Function via PGC-1<svg xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg" style="vertical-align:-0.1993799pt" height="6.51834pt" version="1.1" viewBox="-0.0498162 -6.31896 8.04142 6.51834" width="8.04142pt"><g transform="matrix(.0135,0,0,-0.0135,0,0)"><path id="g5-223" d="M563 442L553 454L479 439C463 404 440 354 416 322H414C389 422 344 454 283 454C151 454 21 310 21 162C21 48 73 -12 135 -12C182 -12 249 19 325 126H327C339 20 368 -12 407 -12C452 -12 507 21 557 110L530 136C508 107 493 92 480 92C462 92 453 123 430 253C459 292 528 386 563 442ZM318 186C290 133 235 76 202 76C175 76 154 108 154 184C154 275 198 406 247 406C288 406 313 294 318 186Z"/></g></svg> Upregulation

The metabolic myocardium is an omnivore and utilizes various carbon substrates to meet its energetic demand. While the adult heart preferentially consumes fatty acids (FAs) over carbohydrates, myocardial fuel plasticity is essential for organismal survival. This metabolic plasticity governing fuel utilization is under robust transcriptional control and studies over the past decade have illuminated members of the nuclear receptor family of factors (e.g., PPAR&#x3B1;) as important regulators of myocardial lipid metabolism. However, given the complexity of myocardial metabolism in health and disease, it is likely that other molecular pathways are likely operative and elucidation of such pathways may provide the foundation for novel therapeutic approaches. We previously demonstrated that Kruppel-like factor 15 (KLF15) is an independent regulator of cardiac lipid metabolism thus raising the possibility that KLF15 and PPAR&#x3B1; operate in a coordinated fashion to regulate myocardial gene expression requisite for lipid oxidation. In the current study, we show that KLF15 binds to, cooperates with, and is required for the induction of canonical PPAR&#x3B1;-mediated gene expression and lipid oxidation in cardiomyocytes. As such, this study establishes a molecular module involving KLF15 and PPAR&#x3B1; and provides fundamental insights into the molecular regulation of cardiac lipid metabolism.

Domenick A. Prosdocimo

Jenine E. John

Lilei Zhang

Elizabeth S. Efraim

Rongli Zhang

Xudong Liao

Mukesh K. Jain

KLF15 and PPAR&#x3B1; Cooperate to Regulate Cardiomyocyte Lipid Gene Expression and Oxidation

PPAR Research

Retracted: A Role for PPAR&#x3b3; in the Regulation of Cytokines in Immune Cells and Cancer

Peroxisome proliferator-activated receptor- (PPAR-) &#x3B3; expression has been shown in thyroid tissue from patients with thyroiditis or Graves&#x2019; disease and furthermore in the orbital tissue of patients with Graves&#x2019; ophthalmopathy (GO), such as in extraocular muscle cells. An increasing body of evidence shows the importance of the (C-X-C motif) receptor 3 (CXCR3) and cognate chemokines (C-X-C motif) ligand (CXCL)9, CXCL10, and CXCL11, in the T helper 1 immune response and in inflammatory diseases such as thyroid autoimmune disorders. PPAR-&#x3B3; agonists show a strong inhibitory effect on the expression and release of CXCR3 chemokines, in vitro, in various kinds of cells, such as thyrocytes, and in orbital fibroblasts, preadipocytes, and myoblasts from patients with GO. Recently, it has been demonstrated that rosiglitazone is involved in a higher risk of heart failure, stroke, and all-cause mortality in old patients. On the contrary, pioglitazone has not shown these effects until now; this favors pioglitazone for a possible use in patients with thyroid autoimmunity. However, further studies are ongoing to explore the use of new PPAR-&#x3B3; agonists in the treatment of thyroid autoimmune disorders.

Silvia Martina Ferrari

Poupak Fallahi

Roberto Vita

Alessandro Antonelli

Salvatore Benvenga

Peroxisome Proliferator-Activated Receptor-&#x3B3; in Thyroid Autoimmunity

Peroxisome-proliferator activated receptor-alpha (PPAR&#x3b1;) is a broadly expressed nuclear hormone receptor and is a transcription factor for diverse target genes possessing a PPAR response element (PPRE) in the promoter region. The PPRE is highly conserved, and PPARs thus regulate transcription of an extensive array of target genes involved in energy metabolism, vascular function, oxidative stress, inflammation, and many other biological processes. PPAR&#x3b1; has potent protective effects against neuronal cell death and microvascular impairment, which have been attributed in part to its antioxidant and anti-inflammatory properties. Here we discuss PPAR&#x3b1;&#x2019;s effects in neurodegenerative and microvascular diseases and also recent clinical findings that identified therapeutic effects of a PPAR&#x3b1; agonist in diabetic microvascular complications.

Elizabeth P. Moran

Jian-xing Ma

Therapeutic Effects of PPAR&#x3b1; on Neuronal Death and Microvascular Impairment

About this journal

PPAR Research publishes articles related to mechanisms involved in the activation of peroxisome proliferator-activated receptors, as well as their role in regulation of cellular differentiation, development, energy homeostasis and metabolic function.

Journal profile

Meet the editorial board

Chief Editor, Dr Xiao-Jie Lu, is dedicated to basic and translational research on liver diseases. His research at Nanjing Medical University, China, focuses&nbsp;on exploring these diseases' underlying mechanisms that may be translatable to novel diagnostic biomarkers or therapeutic targets.

Editor spotlight

Submit your proposal

Do you think there is an emerging area of research that really needs to be highlighted? Or an existing research area that has been overlooked or would benefit from deeper investigation? Raise the profile of a research area by leading a Special Issue.

Special Issues

Author guidelines

Editorial board

Databases and indexing

title

PPAR Research publishes articles related to mechanisms involved in the activation of peroxisome proliferator-activated receptors, as well as their role in regulation of cellular differentiation, development, energy homeostasis and metabolic function.

PPAR Research