PPAR Research https://www.hindawi.com The latest articles from Hindawi © 2019 , Hindawi Limited . All rights reserved. Corrigendum to “Caffeoylquinic Acid-Rich Extract of Aster glehni F. Schmidt Ameliorates Nonalcoholic Fatty Liver through the Regulation of PPARδ and Adiponectin in ApoE KO Mice” Wed, 23 Oct 2019 17:05:03 +0000 http://www.hindawi.com/journals/ppar/2019/5317126/ Yong-Jik Lee, Yoo-Na Jang, Yoon-Mi Han, Hyun-Min Kim, Jong-Min Jeong, Min Jeoung Son, Chang Bae Jin, Hyoung Ja Kim, and Hong Seog Seo Copyright © 2019 Yong-Jik Lee et al. All rights reserved. PPAR-γ Ligand Inhibits Nasopharyngeal Carcinoma Cell Proliferation and Metastasis by Regulating E2F2 Thu, 01 Aug 2019 01:06:10 +0000 http://www.hindawi.com/journals/ppar/2019/8679271/ Purpose. Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear hormone receptor with a key role in lipid metabolism. Previous studies have identified various roles of PPAR-γ in cell cycle progression, cellular proliferation, and tumor progression. However, no report has described a role for PPAR-γ in human nasopharyngeal carcinoma (NPC). Notably, some studies have reported a relationship between PPAR-γ and E2F transcription factor 2 (E2F2), which has been identified as a regulator of cell cycle, apoptosis, and the DNA damage response. Notably, E2F2 has also been reported to correlate with a poor prognosis in patients with various malignancies. Methods. We used immunohistochemical (IHC) and western blot methods to evaluate PPAR-γ and E2F2 expression and function in nonkeratinizing NPC and nasopharyngitis (NPG) tissue samples, as well as western blotting and CCK8 analyses in the NPC cell lines, CNE1 and CNE2. Results. We observed lower levels of PPAR-γ expression in nonkeratinizing NPC tissues compared with NPG tissues and determined an association between a low level of PPAR-γ expression with a more advanced tumor stage. Furthermore, strong E2F2 expression was detected in nonkeratinizing NPC tissues. We further demonstrated that rosiglitazone, a PPAR-γ agonist, reduced E2F2 expression and proliferation in NPC cell lines. Conclusions. Our study results revealed a novel role for the PPAR-γ–E2F2 pathway in controlling NPC cell proliferation and metastasis. Ping-Li Yang, Jia-Shun Wang, Xiao-Mei Cheng, Jing-Cai Chen, Hui Zhu, Xiao-Lan Li, Li Cao, and Wei Tang Copyright © 2019 Ping-Li Yang et al. All rights reserved. 15-Deoxy-∆-12,14-Prostaglandin J2 (15d-PGJ2), an Endogenous Ligand of PPAR-: Function and Mechanism Thu, 01 Aug 2019 01:06:07 +0000 http://www.hindawi.com/journals/ppar/2019/7242030/ 15-Deoxy-∆-12,14-prostaglandin J2 (15d-PGJ2), a natural peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, has been explored in some detail over the last 20 years. By triggering the PPAR-γ signalling pathway, it plays many roles and exerts antitumour, anti-inflammatory, antioxidation, antifibrosis, and antiangiogenesis effects. Although many synthetic PPAR-γ receptor agonists have been developed, as an endogenous product of PPAR-γ receptors, 15d-PGJ2 has beneficial characteristics including rapid expression and the ability to contribute to a natural defence mechanism. In this review, we discuss the latest advances in our knowledge of the biological role of 15d-PGJ2 mediated through PPAR-γ. It is important to understand its structure, synthesis, and functional mechanisms to develop preventive agents and limit the progression of associated diseases. Jingjing Li, Chuanyong Guo, and Jianye Wu Copyright © 2019 Jingjing Li et al. All rights reserved. Corrigendum to “PPARs in Human Neuroepithelial Tumors: PPAR Ligands as Anticancer Therapies for the Most Common Human Neuroepithelial Tumors” Sun, 21 Jul 2019 13:05:06 +0000 http://www.hindawi.com/journals/ppar/2019/4309068/ Elisabetta Benedetti, Renato Galzio, Barbara D’Angelo, Maria Paola Cerù, and Annamaria Cimini Copyright © 2019 Elisabetta Benedetti et al. All rights reserved. Retracted: Possible Role of Interaction between PPARα and Cyclophilin D in Cardioprotection of AMPK against In Vivo Ischemia-Reperfusion in Rats Mon, 15 Jul 2019 09:05:11 +0000 http://www.hindawi.com/journals/ppar/2019/9760941/ PPAR Research Copyright © 2019 PPAR Research. All rights reserved. Activation and Expression of Peroxisome Proliferator-Activated Receptor Alpha Are Associated with Tumorigenesis in Colorectal Carcinoma Wed, 03 Jul 2019 15:05:07 +0000 http://www.hindawi.com/journals/ppar/2019/7486727/ Peroxisome proliferator-activated receptor alpha (PPAR-α) belongs to the PPAR family and plays a critical role in inhibiting cell proliferation and tumorigenesis in various tumors. However, the role of PPAR-α in colorectal tumorigenesis is unclear. In the present study, we found that fenofibrate, a PPAR-α agonist, significantly inhibited cell proliferation and induced apoptosis in colorectal carcinoma cells. In addition, PPAR-α was expressed in the nucleus of colorectal carcinoma cells, and the expression of nuclear PPAR-α increased in colorectal carcinoma tissue compared with that of normal epithelium tissue (P<0.01). The correlation between the expression of nuclear PPAR- and clinicopathological factors was evaluated in human colorectal carcinoma tissues, and the nuclear expression of PPAR-α was significantly higher in well-to-moderately differentiated adenocarcinoma than in mucinous adenocarcinoma (P<0.05). These findings indicate that activation of PPAR-α may be involved in anticancer effects in colorectal carcinomas, and nuclear expression of PPAR-α may be a therapeutic target for colorectal adenocarcinoma treatment. Tatsuya Morinishi, Yasunori Tokuhara, Hiroyuki Ohsaki, Emi Ibuki, Kyuichi Kadota, and Eiichiro Hirakawa Copyright © 2019 Tatsuya Morinishi et al. All rights reserved. Peroxisome Proliferator-Activated Receptor- Antagonizes LOX-1-Mediated Endothelial Injury by Transcriptional Activation of miR-590-5p Mon, 01 Jul 2019 10:05:20 +0000 http://www.hindawi.com/journals/ppar/2019/2715176/ Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is one of the major receptors expressed on the endothelium of arterial wall with a key role in endothelial dysfunction and the development of atherosclerosis. Recent evidence suggested that LOX-1 is upregulated under the condition of insulin resistance and could be suppressed by the antidiabetic drugs. We previously also confirmed that Thiazolidinedione (TZD) has the inhibitory effect on LOX-1 in ox-LDL-induced endothelial cells. However, the underlying mechanism is unclear. Here we showed that Rosiglitazone treatment significantly attenuated the expressions of LOX-1, ICAM-1, VCAM-1, , and the atherosclerotic lesions in ApoE-/- mice with high-fat diet. In vitro, we revealed that Rosiglitazone inhibited LOX-1 by regulating miR-590-5p. Ox-LDL-mediated ICAM-1, VCAM-1, and were significantly reduced by Rosiglitazone, but all reversed after pretreating the cells with antagomiR-590-5p. Induction with Rosiglitazone activated PPAR-γ and promoted its nuclear translocation in cultured human umbilical vein endothelial cells (HUVECs). The nuclear PPAR-γ upregulated the miR-590-5p level through binding to its transcriptional promoter region. Retaining PPAR-γ in cytoplasm by transfecting with plasmid in HUVECs failed to activate miR-590-5p. Mutation of the promoter region of PPAR-γ also reduced the miR-590-5p promoter luciferase activity. Collectively, these data indicated that PPAR-γ may have the therapeutic potential in atherosclerosis via the transcriptional regulation of miR-590-5p in endothelial cells. Lei Xu, Gang Zhao, Hong Zhu, Shijun Wang, Aijun Sun, Yunzeng Zou, and Junbo Ge Copyright © 2019 Lei Xu et al. All rights reserved. Short-Term Activation of Peroxisome Proliferator-Activated Receptors and Induces Tissue-Specific Effects on Lipid Metabolism and Fatty Acid Composition in Male Wistar Rats Wed, 12 Jun 2019 15:05:13 +0000 http://www.hindawi.com/journals/ppar/2019/8047627/ Dietary fatty acids (FAs) affect certain metabolic routes, including pathways controlled by the peroxisome proliferator-activated receptors (PPARs), but tissue-specific effects are not well-defined. Thus, the aim was to compare the metabolic response in hepatic, adipose, and cardiac tissues after treatment with specific PPAR agonists. Male Wistar rats were randomized into three groups: a control group receiving placebo (n=8); a PPARα agonist group receiving WY-14,643 (n=6); and a PPARγ agonist group receiving rosiglitazone (n=6) for 12 days. All animals received a low-fat standard chow diet and were given a daily dose of placebo or agonist orally. Lipids and FA methyl esters were measured in plasma, liver, and heart and gene expression was measured in liver and adipose tissue, while enzyme activities were measured in liver. Treatment with the PPARα agonist was associated with higher liver mass relative to body weight (liver index), lower plasma, and hepatic total cholesterol, as well as lower plasma carnitine and acylcarnitines, compared with control. In heart, PPARα activation leads to overall lower levels of free FAs and specific changes in certain FAs, compared with control. Furthermore, β-oxidation in liver and the enzymatic activities of well-known PPARα targeted genes were higher following PPARα administration. Overall, rats treated with the PPARα agonist had higher hepatic saturated FAs (SFAs) and monounsaturated FAs (MUFAs) and lower n-6 and n-3 PUFAs, compared to control. Treatment with the PPARγ agonist was associated with a lower liver index, lower plasma triglycerides (TAG) and phospholipids, and higher hepatic phospholipids, compared with control. PPARγ target genes were increased specifically in adipose tissue. Moreover, lower total cardiac FAs and SFA and higher cardiac n-6 PUFA were also associated with PPARγ activation. Altogether, there were characteristic effects of PPARα activation in liver and heart, as well as in plasma. PPARγ effects were not only confined to adipose tissue, but specific effects were also seen in liver, heart, and plasma. In conclusion, short-term treatment with PPAR agonists induced tissue-specific effects on FA composition in liver and heart. Moreover, both PPARα and PPARγ activation lowered plasma TAG and phospholipids, most likely through effects on liver and adipose tissue, respectively. In future studies we aim to reveal whether similar patterns can be found through diet-induced activation of specific pathways. Elin Strand, Vegard Lysne, Mari Lausund Grinna, Pavol Bohov, Asbjørn Svardal, Ottar Nygård, Rolf K. Berge, and Bodil Bjørndal Copyright © 2019 Elin Strand et al. All rights reserved. Expression of Concern on “Testosterone Replacement Modulates Cardiac Metabolic Remodeling after Myocardial Infarction by Upregulating PPARα” Tue, 11 Jun 2019 12:05:27 +0000 http://www.hindawi.com/journals/ppar/2019/5137020/ PPAR Research Copyright © 2019 PPAR Research. All rights reserved. PPARG2 Pro12Ala and TNFα -308G>A Polymorphisms Are Not Associated with Heart Failure Development in Patients with Ischemic Heart Disease after Coronary Artery Bypass Grafting Sun, 02 Jun 2019 00:08:27 +0000 http://www.hindawi.com/journals/ppar/2019/1932036/ TNFα and PPARγ are important modulators of metabolism, inflammation, and atherosclerosis. Coronary artery disease is the leading cause of heart failure (HF). The aim of the study was to assess whether polymorphisms of the TNFα (-308G>A) and PPARG2 (Pro12Ala) genes are associated with the risk of developing HF by patients with ischemic heart disease. Methods. 122 patients without HF (aged 63 ± 8.8 years, 85% males) with confirmed coronary artery disease qualified for coronary bypass grafting were enrolled in the study. After the procedure, they were screened for cardiac parameters. Those with elevated NT-proBNP or diminished left ventricular ejection fraction during follow-up were assigned to the HF group (n=78), and the remaining ones to the non-HF group (n=44). The TNFα -308G>A and PPARG2 Pro12Ala polymorphisms were detected using the TaqMan method. Results. The distributions of TNFα -308G>A and PPARG2 Pro12Ala did not differ between the HF and non-HF groups (-308G>A: 16% vs. 11.4% of alleles; Pro12Ala: 23.9% vs. 20.5% of alleles, respectively). IL-6 concentration in the plasma of TNFα A-allele carriers at months 1 and 12 after CABG was higher in the HF group compared to the non-HF group (1 month after CABG: 5.3 ± 3.4 vs. 3.1 ± 2.9, p<0.05; 12 months after CABG: 4.2 ± 3,9 vs. 1.4 ± 1.2, p<0.01, respectively). Both polymorphisms were not related to changes in the plasma TNFα concentration or other parameters related to HF. Conclusions. Our study did not reveal any correlation between the PPARG2 Pro12Ala and TNFα -308G>A polymorphisms and development of HF in patients with ischemic heart disease after coronary bypass grafting. Izabela Wojtkowska, Tomasz A. Bonda, Andrzej Tysarowski, Katarzyna Seliga, Janusz A. Siedlecki, Maria M. Winnicka, and Janina Stępińska Copyright © 2019 Izabela Wojtkowska et al. All rights reserved. Arsenic Trioxide in Synergy with Vitamin D Rescues the Defective VDR-PPAR- Functional Module of Autophagy in Rheumatoid Arthritis Tue, 07 May 2019 10:05:23 +0000 http://www.hindawi.com/journals/ppar/2019/6403504/ Dysregulated autophagy leads to autoimmune diseases including rheumatoid arthritis (RA). Arsenic trioxide (ATO) is a single agent used for the treatment of acute promyelocytic leukemia and is highly promising for other malignancies but is also attractive for RA, although its relationship with autophagy remains to be further clarified and its application optimized. For the first time, we report a defective functional module of autophagy comprising the Vitamin D receptor (VDR), PPAR-γ, microtubule-associated protein 1 light-chain 3 (LC3), and p62 which appears in RA synovial fibroblasts. ATO alleviated RA symptoms by boosting effective autophagic flux through significantly downregulating p62, the inflammation and catabolism protein. Importantly, low-dose ATO synergizes with Vitamin D in RA treatment. Weiyan Wang, Chunling Li, Zhiyi Zhang, and Yue Zhang Copyright © 2019 Weiyan Wang et al. All rights reserved. Retracted: PPARs Expression in Adult Mouse Neural Stem Cells: Modulation of PPARs during Astroglial Differentiaton of NSC Tue, 30 Apr 2019 07:06:06 +0000 http://www.hindawi.com/journals/ppar/2019/5656198/ PPAR Research Copyright © 2019 PPAR Research. All rights reserved. Effects of Dual Peroxisome Proliferator-Activated Receptors and Activation in Two Rat Models of Neuropathic Pain Wed, 17 Apr 2019 10:05:25 +0000 http://www.hindawi.com/journals/ppar/2019/2630232/ Neuropathic pain is a growing healthcare problem causing a global burden. Currently used analgesics such as opioids are associated with adverse effects; urging the need for safer alternatives. Here we aimed to investigate the potential analgesic effects of tesaglitazar; dual peroxisome proliferator-activated receptors α and γ (PPARα and γ) agonist in rat models of neuropathic pain. This study also aimed to investigate the modulation of the transient receptor potential vanilloid 1 (TRPV1) receptor activity by tesaglitazar which could provide a potential mechanism that underlie tesaglitazar antinociceptive effects. Von Frey filaments were used to determine the paw withdrawal threshold (PWT) in adult male Sprague Dawley rats (180-250g) following i.p. injection of streptozotocin (STZ) or cisplatin, which were used as models of neuropathic pain. Antinociceptive effects of tesaglitazar were determined 6 hours after drug administration. Cobalt influx assays in cultured dorsal root ganglia (DRG) neurons were used to study the effects of tesaglitazar preincubation on capsaicin-evoked cobalt influx. Both cisplatin and STZ produced a significant decrease in PWT. The higher dose of tesaglitazar (20μg/kg) significantly restored PWT in both neuropathic pain models (P<0.05). 10μM capsaicin produced a robust cobalt response in DRG neurons. Preincubation of DRG neurones with tesaglitazar 6 hours prior to stimulation with capsaicin significantly reduce capsaicin-evoked cobalt responses in a PPARα and PPARγ dependent fashion (P<0.05). In conclusion, tesaglitazar produced significant analgesic effects in STZ and cisplatin-induced neuropathy, possibly by modulating TRPV1 receptor activity. This may be of potential benefit in clinical practice dealing with peripheral neuropathy. Mohammad Alsalem, Mansour Haddad, Sara A. Aldossary, Heba Kalbouneh, Belal Azab, Aala Dweik, Amer Imraish, and Khalid El-Salem Copyright © 2019 Mohammad Alsalem et al. All rights reserved. Corrigendum to “Pioglitazone Attenuates Drug-Eluting Stent-Induced Proinflammatory State in Patients by Blocking Ubiquitination of PPAR” Sun, 03 Mar 2019 14:05:18 +0000 http://www.hindawi.com/journals/ppar/2019/3298724/ Zhongxia Wang, Tao Zhang, Lizhe Sun, Ruifeng Li, Yuanyuan Wei, Xiaojuan Fan, Zuyi Yuan, Junhui Liu, and Tao Chen Copyright © 2019 Zhongxia Wang et al. All rights reserved. Rosiglitazone, a Ligand to PPAR, Improves Blood Pressure and Vascular Function through Renin-Angiotensin System Regulation Sun, 03 Feb 2019 12:05:14 +0000 http://www.hindawi.com/journals/ppar/2019/1371758/ Rosiglitazone (RGZ), a peroxisome proliferator-activated receptor gamma (PPARγ) ligand, has been reported to act as insulin sensitizer and exert cardiovascular actions. In this work, we hypothesized that RGZ exerts a PPARγ–dependent regulation of blood pressure through modulation of angiotensin-converting enzyme (ACE)-type 2 (ACE2)/angiotensin-(1-7)/angiotensin II type-2 receptor (AT2R) axis in an experimental model of high blood pressure. We carried on experiments in normotensive (Sham) and aortic coarctation (AoCo)-induced hypertensive male Wistar rats. Both sham and AoCo rats were treated 7 days with vehicle (V), RGZ (5 mg/kg/day), or RGZ+BADGE (120 mg/kg/day) post-coarctation. We measured blood pressure and vascular reactivity on aortic rings, as well as the expression of renin-angiotensin system (RAS) proteins. We found that RGZ treatment in AoCo group decreases blood pressure values and improves vascular response to acetylcholine, both parameters dependent on PPARγ-stimulation. RGZ lowered serum angiotensin II (AngII) but increased Ang-(1-7) levels. It also decreased 8-hydroxy-2′-deoxyguanosine (8-OH-2dG), malondialdehyde (MDA), and improved the antioxidant capacity. Regarding protein expression of RAS, RGZ decreases ACE and angiotensin II type 1 receptor (AT1R) and improved ACE2, AT2R, and Mas receptor in AoCo rats. Additionally, an in silico analysis revealed that 5′UTR regions of RAS and PPARγ share motifs with a transcriptional regulatory role. We conclude that RGZ lowers blood pressure values by increasing the expression of RAS axis proteins ACE2 and AT2R, decreasing the levels of AngII and increasing levels of Ang-(1-7) in a PPARγ-dependent manner. The in silico analysis is a valuable tool to predict the interaction between PPARγ and RAS. María Sánchez-Aguilar, Luz Ibarra-Lara, Leonardo Del Valle-Mondragón, María Esther Rubio-Ruiz, Alicia G. Aguilar-Navarro, Absalom Zamorano-Carrillo, Margarita del Carmen Ramírez-Ortega, Gustavo Pastelín-Hernández, and Alicia Sánchez-Mendoza Copyright © 2019 María Sánchez-Aguilar et al. All rights reserved. 6-Gingerol Normalizes the Expression of Biomarkers Related to Hypertension via PPARδ in HUVECs, HEK293, and Differentiated 3T3-L1 Cells Sun, 16 Dec 2018 07:40:07 +0000 http://www.hindawi.com/journals/ppar/2018/6485064/ Hypertension is a disease with a high prevalence and high mortality rates worldwide. In addition, various factors, such as genetic predisposition, lifestyle factors, and the abnormality of organs related to blood pressure, are involved in the development of hypertension. However, at present, there are few available drugs for hypertension that do not induce side effects. Although the therapeutic effects of ginger on hypertension are well established, the precise mechanism has not been elucidated. Therefore, this study was designed to evaluate the antihypertensive mechanism of 6-gingerol, one of the main ingredients of ginger, and to assist in the development of new drugs for hypertension without side effects. The antihypertensive effects and mechanism of 6-gingerol were identified through reverse transcription polymerase chain reaction (RT-PCR), western blotting, and immunocytochemical staining for biomarkers involved in hypertension in human umbilical vein endothelial cells (HUVECs), human embryonal kidney cells (HEK293 cells), and mouse preadipocytes (3T3-L1 cells). The lipid accumulation in differentiated 3T3-L1 cells was evaluated by using Oil Red O staining. 6- Gingerol increased the level of phosphorylated endothelial nitric oxide synthase (eNOS) protein but decreased that of vascular cell adhesion protein 1 (VCAM1) and tumor necrosis factor alpha (TNFα) in HUVECs. In HEK293 cells, the expression of the epithelial sodium channel (ENaC) protein was reduced by 6-gingerol. Lipid accumulation was attenuated by 6-gingerol treatment in differentiated 3T3-L1 cells. These effects were regulated via peroxisome proliferator-activated receptor delta (PPARδ). 6-Gingerol ameliorated the expression of biomarkers involved in the development of hypertension through PPARδ in HUVECs, HEK293, and differentiated 3T3-L1 cells. Yong-Jik Lee, Yoo-Na Jang, Yoon-Mi Han, Hyun-Min Kim, and Hong Seog Seo Copyright © 2018 Yong-Jik Lee et al. All rights reserved. Crosstalk between MicroRNAs and Peroxisome Proliferator-Activated Receptors and Their Emerging Regulatory Roles in Cardiovascular Pathophysiology Wed, 05 Dec 2018 06:54:16 +0000 http://www.hindawi.com/journals/ppar/2018/8530371/ Peroxisome proliferator-activated receptors (PPARs) play vital roles in cardiovascular pathophysiology, such as energy balance, cell proliferation/apoptosis, inflammatory response, and adipocyte differentiation. These vital roles make PPARs potential targets for therapeutic prevention of cardiovascular diseases (CVDs). Emerging evidence indicates that the crosstalk of microRNAs (miRNAs) and PPARs contributes greatly to CVD pathogenesis. PPARs are inhibited by miRNAs at posttranscriptional mechanisms in the progress of pulmonary hypertension and vascular dysfunction involving cell proliferation/apoptosis, communication, and normal function of endothelial cells and vascular smooth muscle cells. In the development of atherosclerosis and stroke, the activation of PPARs could change the transcripts of target miRNA through miRNA signalling. Furthermore, the mutual regulation of PPARs and miRNAs involves cell proliferation/apoptosis, cardiac remodeling, and dysfunction in heart diseases. In addition, obesity, an important cardiovascular risk, is modulated by the regulatory axis of PPARs/miRNAs, including adipogenesis, adipocyte dysfunction, insulin resistance, and macrophage polarization in adipose tissue. In this review, the crosstalk of PPARs and miRNAs and their emerging regulatory roles are summarized in the context of CVDs and risks. This provides an understanding of the underlying mechanism of the biological process related to CVD pathophysiology involving the interaction of PPARs and miRNAs and will lead to the development of PPARs/miRNAs as effective anti-CVD medications. Yin-Feng Zhang, Hai-Ming Xu, Fei Yu, Man Wang, Meng-Yang Li, Tao Xu, Yan-Yan Gao, Jian-Xun Wang, and Pei-Feng Li Copyright © 2018 Yin-Feng Zhang et al. All rights reserved. Erratum to “Inducible Conditional Vascular-Specific Overexpression of Peroxisome Proliferator-Activated Receptor Beta/Delta Leads to Rapid Cardiac Hypertrophy” Mon, 29 Oct 2018 00:00:00 +0000 http://www.hindawi.com/journals/ppar/2018/5480829/ Kay-Dietrich Wagner, Ana Vukolic, Delphine Baudouy, Jean-François Michiels, and Nicole Wagner Copyright © 2018 Kay-Dietrich Wagner et al. All rights reserved. Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer’s Disease Sun, 21 Oct 2018 06:30:43 +0000 http://www.hindawi.com/journals/ppar/2018/2010675/ Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPARγ more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPARγ agonists influence various pathologies in AD with emphasis on development of novel selective PPARγ modulators. Manoj Govindarajulu, Priyanka D. Pinky, Jenna Bloemer, Nila Ghanei, Vishnu Suppiramaniam, and Rajesh Amin Copyright © 2018 Manoj Govindarajulu et al. All rights reserved. Effects of Pioglitazone on Nonalcoholic Fatty Liver Disease in the Absence of Constitutive Androstane Receptor Expression Thu, 27 Sep 2018 06:53:20 +0000 http://www.hindawi.com/journals/ppar/2018/9568269/ Nonalcoholic fatty liver disease or steatohepatitis (NAFLD/NASH) is a fatty liver disease that is closely related to obesity, diabetes, and dyslipidemia. Pioglitazone, which was developed as an antidiabetic drug, is known to improve NALFD. Pioglitazone is metabolized by multiple cytochrome P450 (CYP) enzymes, which are regulated by the xenobiotic receptor constitutive androstane receptor (CAR). In this study, we investigated the effects of pioglitazone on NAFLD by absence of CAR activity under high-fat (HF)-fed conditions. CAR-/- mice showed significant improvement in NALFD after 12 weeks of pioglitazone treatment compared to wild-type mice. This improvement in NAFLD persisted in CAR-/- mice regardless of blood pioglitazone concentration. The expression of lipogenesis genes in the liver, sterol-regulatory element binding protein-1c (SREBP-1c), and stearoyl-CoA desaturase (SCD)-1 was decreased after pioglitazone treatment in HF-fed CAR-/- mice. In addition, the expression of peroxisome proliferator-activated receptor gamma 2 (PPARγ2) was decreased by pioglitazone in HF-fed CAR-/- mice. Changes in SREBP-1c and PPAR γ2 remained constant over short-term (6 h) pioglitazone and lipid injection. Our results showed that NAFLD was improved significantly by pioglitazone in a CAR deletion state. These results might be valuable because they suggest that interaction with CAR and pioglitazone/PPARγ2 may be important in regulating gene expression associated with NAFLD. Hwa Young Ahn, Hwan Hee Kim, Ji-Yeon Hwang, Changhun Park, Bo Youn Cho, and Young Joo Park Copyright © 2018 Hwa Young Ahn et al. All rights reserved. A Reduction in ADAM17 Expression Is Involved in the Protective Effect of the PPAR-α Activator Fenofibrate on Pressure Overload-Induced Cardiac Hypertrophy Thu, 19 Jul 2018 00:00:00 +0000 http://www.hindawi.com/journals/ppar/2018/7916953/ The peroxisome proliferator-activated receptor-α (PPAR-α) agonist fenofibrate ameliorates cardiac hypertrophy; however, its mechanism of action has not been completely determined. Our previous study indicated that a disintegrin and metalloproteinase-17 (ADAM17) is required for angiotensin II-induced cardiac hypertrophy. This study aimed to determine whether ADAM17 is involved in the protective action of fenofibrate against cardiac hypertrophy. Abdominal artery constriction- (AAC-) induced hypertensive rats were used to observe the effects of fenofibrate on cardiac hypertrophy and ADAM17 expression. Primary cardiomyocytes were pretreated with fenofibrate (10 μM) for 1 hour before being stimulated with angiotensin II (100 nM) for another 24 hours. Fenofibrate reduced the ratios of left ventricular weight to body weight (LVW/BW) and heart weight to body weight (HW/BW), left ventricular anterior wall thickness (LVAW), left ventricular posterior wall thickness (LVPW), and ADAM17 mRNA and protein levels in left ventricle in AAC-induced hypertensive rats. Similarly, in vitro experiments showed that fenofibrate significantly attenuated angiotensin II-induced cardiac hypertrophy and diminished ADAM17 mRNA and protein levels in primary cardiomyocytes stimulated with angiotensin II. In summary, a reduction in ADAM17 expression is associated with the protective action of PPAR-α agonists against pressure overload-induced cardiac hypertrophy. Si-Yu Zeng, Hui-Qin Lu, Qiu-Jiang Yan, and Jian Zou Copyright © 2018 Si-Yu Zeng et al. All rights reserved. Combined Rosiglitazone and Forskolin Have Neuroprotective Effects in SD Rats after Spinal Cord Injury Thu, 21 Jun 2018 00:00:00 +0000 http://www.hindawi.com/journals/ppar/2018/3897478/ The peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist rosiglitazone inhibits NF-κB expression and endogenous neural stem cell differentiation into neurons and reduces the inflammatory cascade after spinal cord injury (SCI). The aim of this study was to explore the mechanisms underlying rosiglitazone-mediated neuroprotective effects and regulation of the balance between the inflammatory cascade and generation of endogenous spinal cord neurons by using a spinal cord-derived neural stem cell culture system as well as SD rat SCI model. Activation of PPAR-γ could promote neural stem cell proliferation and inhibit PKA expression and neuronal formation in vitro. In the SD rat SCI model, the rosiglitazone + forskolin group showed better locomotor recovery compared to the rosiglitazone and forskolin groups. MAP2 expression was higher in the rosiglitazone + forskolin group than in the rosiglitazone group, NF-κB expression was lower in the rosiglitazone + forskolin group than in the forskolin group, and NeuN expression was higher in the rosiglitazone + forskolin group than in the forskolin group. PPAR-γ activation likely inhibits NF-κB, thereby reducing the inflammatory cascade, and PKA activation likely promotes neuronal cell regeneration. Qing-qi Meng, Wei Lei, Hao Chen, Zhen-cheng Feng, Li-qiong Hu, Xing-liang Zhang, and Siming Li Copyright © 2018 Qing-qi Meng et al. All rights reserved. Treatment with Lobeglitazone Attenuates Hepatic Steatosis in Diet-Induced Obese Mice Wed, 13 Jun 2018 00:00:00 +0000 http://www.hindawi.com/journals/ppar/2018/4292509/ Nonalcoholic fatty liver disease (NAFLD) is strongly associated with insulin resistance. The peroxisome proliferator-activated receptor (PPAR) activators, thiazolidinediones, (TZDs), are insulin sensitizers used as a treatment for NAFLD. However, TZDs are a controversial treatment for NAFLD because of conflicting results regarding hepatic steatosis and fibrosis. To evaluate a possible effective drug for treatment of NAFLD, we investigated the effects of a newly developed TZD, lobeglitazone, with an emphasis on hepatic lipid metabolism. Lobeglitazone treatment for 4 weeks in high fat diet- (HFD-) induced obese mice (HL group) improved insulin resistance and glucose intolerance compared to HFD-induced obese mice (HU group). The gene levels related to hepatic gluconeogenesis also decreased after treatment by lobeglitazone. The livers of mice in the HL group showed histologically reduced lipid accumulation, with lowered total plasma cholesterol and triglyceride levels. In addition, the HL group significantly decreased the hepatic expression of genes associated with lipid synthesis, cholesterol biosynthesis, and lipid droplet development and increased the hepatic expression of genes associated with fatty acid β-oxidation, thus suggesting that lobeglitazone decreased hepatic steatosis and reversed hepatic lipid dysregulation. Livers with steatohepatitis contained increased levels of PPARγ and phosphorylated PPARγ at serine 273, leading to downregulation of expression of genes associated with insulin sensitivity. Notably, the treatment of lobeglitazone increased the protein levels of PPARα and diminished levels of PPARγ phosphorylated at serine 273, which were increased by a HFD, suggesting that induction of PPARα and posttranslational modification of PPARγ in livers by lobeglitazone might be an underlying mechanism of the improvement seen in NAFLD. Taken together, our data showed that lobeglitazone might be an effective treatment for NAFLD. Sorim Choung, Kyong Hye Joung, Bo Ram You, Sang Ki Park, Hyun Jin Kim, and Bon Jeong Ku Copyright © 2018 Sorim Choung et al. All rights reserved. Expression of GPR43 in Brown Adipogenesis Is Enhanced by Rosiglitazone and Controlled by PPARγ/RXR Heterodimerization Wed, 16 May 2018 07:44:19 +0000 http://www.hindawi.com/journals/ppar/2018/1051074/ GPR43, a G-protein coupled receptor recognizing short-chain fatty acids, has been reported to participate in many biological functions of white adipocytes, such as adipogenesis and lipolysis. However, the functional role of GPR43 in brown adipocytes is still not clear. In this study, we investigated the effects of the PPARγ agonist rosiglitazone on GPR43 expression in brown adipogenesis. The results demonstrated that GPR43 was expressed during the late phase of brown adipocyte differentiation, which could be further augmented by adipogenic agent rosiglitazone treatment. The PPARγ/RXR heterodimerization was found to be the key transcription factor for this enhancing effect of rosiglitazone on GPR43 expression. Taken together, these results suggested GPR43 levels might be regulated by PPARγ-activated events during brown adipocytes differentiation and reflect the adipogenesis status of brown adipocytes. Jiamiao Hu, Arong Zhou, Peter C. K. Cheung, Baodong Zheng, Shaoxiao Zeng, and Shaoling Lin Copyright © 2018 Jiamiao Hu et al. All rights reserved. Inhibitory Effects of a Novel PPAR-γ Agonist MEKT1 on Pomc Expression/ACTH Secretion in AtT20 Cells Mon, 23 Apr 2018 00:00:00 +0000 http://www.hindawi.com/journals/ppar/2018/5346272/ Although therapeutic effects of the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists rosiglitazone and pioglitazone against Cushing’s disease have been reported, their effects are still controversial and inconsistent. We therefore examined the effects of a novel PPAR-γ agonist, MEKT1, on Pomc expression/ACTH secretion using murine corticotroph-derived AtT20 cells and compared its effects with those of rosiglitazone and pioglitazone. AtT20 cells were treated with either 1 nM~10 μM MEKT1, rosiglitazone, or pioglitazone for 24 hours. Thereafter, their effects on proopiomelanocortin gene (Pomc) mRNA expression were studied by qPCR and the Pomc promoter (−703/+58) activity was demonstrated by luciferase assay. Pomc mRNA expression and promoter activity were significantly inhibited by MEKT1 at 10 μM compared to rosiglitazone and pioglitazone. SiRNA-mediated PPAR-γ knockdown significantly abrogated MEKT1-mediated Pomc mRNA suppression. ACTH secretion from AtT20 cells was also significantly inhibited by MEKT1. Deletion/point mutant analyses of Pomc promoter indicated that the MEKT1-mediated suppression was mediated via NurRE, TpitRE, and NBRE at −404/383, −316/309, and −69/63, respectively. Moreover, MEKT1 significantly suppressed Nur77, Nurr1, and Tpit mRNA expression. MEKT1 also was demonstrated to inhibit the protein-DNA interaction of Nur77/Nurr1-NurRE, Tpit-TpitRE, and Nur77-NBRE by ChIP assay. Taken together, it is suggested that MEKT1 could be a novel therapeutic medication for Cushing’s disease. Rehana Parvin, Erika Noro, Akiko Saito-Hakoda, Hiroki Shimada, Susumu Suzuki, Kyoko Shimizu, Hiroyuki Miyachi, Atsushi Yokoyama, and Akira Sugawara Copyright © 2018 Rehana Parvin et al. All rights reserved. Cellular and Biophysical Pipeline for the Screening of Peroxisome Proliferator-Activated Receptor Beta/Delta Agonists: Avoiding False Positives Thu, 12 Apr 2018 00:00:00 +0000 http://www.hindawi.com/journals/ppar/2018/3681590/ Peroxisome proliferator-activated receptor beta/delta (PPARß/δ) is considered a therapeutic target for metabolic disorders, cancer, and cardiovascular diseases. Here, we developed one pipeline for the screening of PPARß/δ agonists, which reduces the cost, time, and false-positive hits. The first step is an optimized 3-day long cellular transactivation assay based on reporter-gene technology, which is supported by automated liquid-handlers. This primary screening is followed by a confirmatory transactivation assay and by two biophysical validation methods (thermal shift assay (TSA) and (ANS) fluorescence quenching), which allow the calculation of the affinity constant, giving more information about the selected hits. All of the assays were validated using well-known commercial agonists providing trustworthy data. Furthermore, to validate and test this pipeline, we screened a natural extract library (560 extracts), and we found one plant extract that might be interesting for PPARß/δ modulation. In conclusion, our results suggested that we developed a cheaper and more robust pipeline that goes beyond the single activation screening, as it also evaluates PPARß/δ tertiary structure stabilization and the ligand affinity constant, selecting only molecules that directly bind to the receptor. Moreover, this approach might improve the effectiveness of the screening for agonists that target PPARß/δ for drug development. Natália Bernardi Videira, Fernanda Aparecida Heleno Batista, Artur Torres Cordeiro, and Ana Carolina Migliorini Figueira Copyright © 2018 Natália Bernardi Videira et al. All rights reserved. The Hepatoprotection by Oleanolic Acid Preconditioning: Focusing on PPARα Activation Mon, 02 Apr 2018 00:00:00 +0000 http://www.hindawi.com/journals/ppar/2018/3180396/ Objective. Previous studies have characterized the hepatoprotective and anti-inflammatory properties of oleanolic acid (OA). This study aimed to investigate the molecular mechanisms of OA hepatoprotection in concanavalin A- (ConA-) induced acute liver injury. Materials and Methods. ConA (20 mg/kg) was intravenously injected to induce acute liver injury in Balb/C mice. OA pretreatment (20, 40, and 80 mg/kg) was administered subcutaneously once daily for 3 consecutive days prior to treatment with ConA; 2, 8, and 24 h after ConA injection, the levels of serum liver enzymes and the histopathology of major factors and inflammatory cytokines were determined. Results. OA reduced the release of serum liver enzymes and inflammatory factors and prevented ConA mediated damage to the liver. OA elevated the expression levels of peroxisome proliferator-activated receptor alpha (PPARα) and decreased the phosphorylation of c-Jun NH2-terminal kinase (JNK). Conclusion. OA exhibits anti-inflammatory properties during ConA-induced acute liver injury by attenuating apoptosis and autophagy through activation of PPARα and downregulation of JNK signaling. Wenwen Wang, Kan Chen, Yujing Xia, Wenhui Mo, Fan Wang, Weiqi Dai, and Peiqin Niu Copyright © 2018 Wenwen Wang et al. All rights reserved. Treatment of Diabetic Mice with a Combination of Ketogenic Diet and Aerobic Exercise via Modulations of PPARs Gene Programs Tue, 20 Mar 2018 00:00:00 +0000 http://www.hindawi.com/journals/ppar/2018/4827643/ Type 2 diabetes is a prevalent chronic disease arising as a serious public health problem worldwide. Diet intervention is considered to be a critical strategy in glycemic control of diabetic patients. Recently, the low-carbohydrate ketogenic diet is shown to be effective in glycemic control and weight loss. However, hepatic lipid accumulation could be observed in mice treated with ketogenic diet. On the other hand, exercise is a well-known approach for treating nonalcoholic fatty liver disease. We thus hypothesize that the combination of ketogenic diet and exercise could improve insulin sensitivity, while minimizing adverse effect of hepatic steatosis. In order to test this hypothesis, we established diabetic mice model with streptozotocin (STZ) and divided them into control group, ketogenic diet group, and ketogenic diet with aerobic exercise group. We found that after six weeks of intervention, mice treated with ketogenic diet and ketogenic diet combined with exercise both have lower body weights, HbAlc level, HOMA index, and improvements in insulin sensitivity, compared with diabetes group. In addition, mice in ketogenic diet intervention exhibited hepatic steatosis shown by serum and hepatic parameters, as well as histochemistry staining in the liver, which could be largely relieved by exercise. Furthermore, gene analysis revealed that ketogenic diet in combination with exercise reduced PPARγ and lipid synthetic genes, as well as enhancing PPARα and lipid β-oxidation gene program in the liver compared to those in ketogenic diet without exercise. Overall, the present study demonstrated that the combination of ketogenic diet and a moderate-intensity aerobic exercise intervention improved insulin sensitivity in diabetic mice, while avoiding hepatic steatosis, which provided a novel strategy in the combat of diabetes. Qiang Zhang, Lingyan Xu, Jie Xia, Dongmei Wang, Min Qian, and Shuzhe Ding Copyright © 2018 Qiang Zhang et al. All rights reserved. High Glucose Induces Autophagy through PPARγ-Dependent Pathway in Human Nucleus Pulposus Cells Thu, 01 Mar 2018 00:00:00 +0000 http://www.hindawi.com/journals/ppar/2018/8512745/ Diabetes mellitus is a multiorgan disorder affecting many types of connective tissues, including bone and cartilage. High glucose could accelerate the autophagy in nucleus pulposus (NP) cells. In our present study, we investigated whether peroxisome proliferator-activated receptor γ (PPAR-γ) pathway is involved into autophagy regulation in NP cells under high glucose condition. After NP cells were treated with different high glucose concentrations for 72 hours, the rate of autophagy increased. Moreover, the levels of PPARγ, Beclin-1, and LC3II were significantly increased and p62 was significantly decreased compared to control group. Then, NP cells were treated with high glucose plus PPARγ agonist or PPARγ antagonist, respectively. The rate of autophagy and the levels of Beclin-1 and LC3II increased, but p62 decreased when PPARγ agonist was used. On the contrary, the rate of autophagy and the levels of Beclin-1 and LC3II decreased, while p62 increased when PPARγ antagonist was added. These results suggested that autophagy induced by high glucose in NP cells was through PPARγ-dependent pathway. Chang Jiang, Shuhao Liu, Yuanwu Cao, and Hongping Shan Copyright © 2018 Chang Jiang et al. All rights reserved. PPARγ Antagonizes Hypoxia-Induced Activation of Hepatic Stellate Cell through Cross Mediating PI3K/AKT and cGMP/PKG Signaling Thu, 01 Mar 2018 00:00:00 +0000 http://www.hindawi.com/journals/ppar/2018/6970407/ Background and Aims. Accumulating evidence reveals that PPARγ plays a unique role in the regulation of hepatic fibrosis and hepatic stellate cells (HSCs) activation. This study was aimed at investigating the role of PPARγ in hypoxia-induced hepatic fibrogenesis and its possible mechanism. Methods. Rats used for CCl4-induced hepatic fibrosis model were exposed to hypoxia for 8 hours each day. Rats exposed to hypoxia were treated with or without the PPARγ agonist rosiglitazone. Liver sections were stained with HE and Sirius red staining 8 weeks later. HSCs were exposed to hypoxic environment in the presence or absence of rosiglitazone, and expression of PPARγ and two fibrosis markers, α-SMA and desmin, were measured using western blot and immunofluorescence staining. Next, levels of PPARγ, α-SMA, and desmin as well as PKG and cGMP activity were detected using PI3K/AKT and a cGMP activator or inhibitor. Results. Hypoxia promoted the induction and progress of hepatic fibrosis and HSCs activation. Meanwhile, rosiglitazone significantly antagonized the effects induced by hypoxia. Signaling by sGC/cGMP/PKG promoted the inhibitory effect of PPARγ on hypoxia-induced activation of HSCs. Moreover, PI3K/AKT signaling or PDE5 blocked the above response of PPARγ. Conclusion. sGC/cGMP/PKG and PI3K/AKT signals act on PPARγ synergistically to attenuate hypoxia-induced HSC activation. Qinghui Zhang, Shihao Xiang, Qingqian Liu, Tao Gu, Yongliang Yao, and Xiaojie Lu Copyright © 2018 Qinghui Zhang et al. All rights reserved.