Pub Date : 2018-03-01eCollection Date: 2018-01-01DOI: 10.1155/2018/6970407
Qinghui Zhang, Shihao Xiang, Qingqian Liu, Tao Gu, Yongliang Yao, Xiaojie Lu
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.
{"title":"PPAR<i>γ</i> Antagonizes Hypoxia-Induced Activation of Hepatic Stellate Cell through Cross Mediating PI3K/AKT and cGMP/PKG Signaling.","authors":"Qinghui Zhang, Shihao Xiang, Qingqian Liu, Tao Gu, Yongliang Yao, Xiaojie Lu","doi":"10.1155/2018/6970407","DOIUrl":"https://doi.org/10.1155/2018/6970407","url":null,"abstract":"<p><strong>Background and aims: </strong>Accumulating evidence reveals that PPAR<i>γ</i> 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 PPAR<i>γ</i> in hypoxia-induced hepatic fibrogenesis and its possible mechanism.</p><p><strong>Methods: </strong>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 PPAR<i>γ</i> 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 PPAR<i>γ</i> and two fibrosis markers, <i>α</i>-SMA and desmin, were measured using western blot and immunofluorescence staining. Next, levels of PPAR<i>γ</i>, <i>α</i>-SMA, and desmin as well as PKG and cGMP activity were detected using PI3K/AKT and a cGMP activator or inhibitor.</p><p><strong>Results: </strong>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 PPAR<i>γ</i> on hypoxia-induced activation of HSCs. Moreover, PI3K/AKT signaling or PDE5 blocked the above response of PPAR<i>γ</i>.</p><p><strong>Conclusion: </strong>sGC/cGMP/PKG and PI3K/AKT signals act on PPAR<i>γ</i> synergistically to attenuate hypoxia-induced HSC activation.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2018 ","pages":"6970407"},"PeriodicalIF":2.9,"publicationDate":"2018-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2018/6970407","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36036570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-02-01eCollection Date: 2018-01-01DOI: 10.1155/2018/5289859
Shuqi Xu, Xuanfu Xu
Peroxisome proliferator-activated receptor-γ (PPARγ) is a class of ligand-activated nuclear transcription factors, which is a member of type II nuclear receptor superfamily. Previous studies demonstrate that PPARγ is expressed in a variety of tumor tissues and is closely associated with the proliferation and prognosis of digestive system tumors by its roles in mediation of cell differentiation, induction of cell apoptosis, and inhibition of cell proliferation.
{"title":"Research Advances in the Correlation between Peroxisome Proliferator-Activated Receptor-<i>γ</i> and Digestive Cancers.","authors":"Shuqi Xu, Xuanfu Xu","doi":"10.1155/2018/5289859","DOIUrl":"https://doi.org/10.1155/2018/5289859","url":null,"abstract":"<p><p>Peroxisome proliferator-activated receptor-<i>γ</i> (PPAR<i>γ</i>) is a class of ligand-activated nuclear transcription factors, which is a member of type II nuclear receptor superfamily. Previous studies demonstrate that PPAR<i>γ</i> is expressed in a variety of tumor tissues and is closely associated with the proliferation and prognosis of digestive system tumors by its roles in mediation of cell differentiation, induction of cell apoptosis, and inhibition of cell proliferation.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2018 ","pages":"5289859"},"PeriodicalIF":2.9,"publicationDate":"2018-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2018/5289859","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35864431","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-02-01eCollection Date: 2018-01-01DOI: 10.1155/2018/6079101
Rui Kong, Hui Luo, Nan Wang, Jingjing Li, Shizan Xu, Kan Chen, Jiao Feng, Liwei Wu, Sainan Li, Tong Liu, Xiya Lu, Yujing Xia, Yanhong Shi, Yingqun Zhou, Weigang He, Qi Dai, Yuejuan Zheng, Jie Lu
Portulaca oleracea L. is a traditional Chinese medicine, which has been used as adjuvant therapy for inflammatory bowel disease (IBD). However, the mechanism of its activity in IBD still remains unclear. Since previous studies have documented the anti-inflammatory effect of peroxisome proliferator activated receptors-γ (PPAR-γ), Portulaca regulation of PPAR-γ in inflammation was examined in current study. Ulcerative colitis (UC) was generated by 5% dextran sulfate sodium (DSS) in mice and four groups were established as normal control, DSS alone, DSS plus mesalamine, and DSS plus Portulaca. Severity of UC was evaluated by body weight, stool blood form, and length of colorectum. Inflammation was examined by determination of inflammatory cytokines (TNF-a, IL-6, and IL-1a). Portulaca extract was able to attenuate development of UC in DSS model similar to the treatment of mesalazine. Moreover, Portulaca extract inhibited proinflammatory cytokines release and reduced the level of DSS-induced NF-κB phosphorylation. Furthermore, Portulaca extract restored PPAR-γ level, which was reduced by DSS. In addition, Portulaca extract protected DSS induced apoptosis in mice. In conclusion, Portulaca extract can alleviate colitis in mice through regulation of inflammatory reaction, apoptosis, and PPAR-γ level; therefore, Portulaca extract can be a potential candidate for the treatment of IBD.
{"title":"<i>Portulaca</i> Extract Attenuates Development of Dextran Sulfate Sodium Induced Colitis in Mice through Activation of PPAR<i>γ</i>.","authors":"Rui Kong, Hui Luo, Nan Wang, Jingjing Li, Shizan Xu, Kan Chen, Jiao Feng, Liwei Wu, Sainan Li, Tong Liu, Xiya Lu, Yujing Xia, Yanhong Shi, Yingqun Zhou, Weigang He, Qi Dai, Yuejuan Zheng, Jie Lu","doi":"10.1155/2018/6079101","DOIUrl":"https://doi.org/10.1155/2018/6079101","url":null,"abstract":"<p><p><i>Portulaca oleracea</i> L. is a traditional Chinese medicine, which has been used as adjuvant therapy for inflammatory bowel disease (IBD). However, the mechanism of its activity in IBD still remains unclear. Since previous studies have documented the anti-inflammatory effect of peroxisome proliferator activated receptors-<i>γ</i> (PPAR-<i>γ</i>), <i>Portulaca</i> regulation of PPAR-<i>γ</i> in inflammation was examined in current study. Ulcerative colitis (UC) was generated by 5% dextran sulfate sodium (DSS) in mice and four groups were established as normal control, DSS alone, DSS plus mesalamine, and DSS plus <i>Portulaca</i>. Severity of UC was evaluated by body weight, stool blood form, and length of colorectum. Inflammation was examined by determination of inflammatory cytokines (TNF-a, IL-6, and IL-1a). <i>Portulaca</i> extract was able to attenuate development of UC in DSS model similar to the treatment of mesalazine. Moreover, <i>Portulaca</i> extract inhibited proinflammatory cytokines release and reduced the level of DSS-induced NF-<i>κ</i>B phosphorylation. Furthermore, <i>Portulaca</i> extract restored PPAR-<i>γ</i> level, which was reduced by DSS. In addition, <i>Portulaca</i> extract protected DSS induced apoptosis in mice. In conclusion, <i>Portulaca</i> extract can alleviate colitis in mice through regulation of inflammatory reaction, apoptosis, and PPAR-<i>γ</i> level; therefore, <i>Portulaca</i> extract can be a potential candidate for the treatment of IBD.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2018 ","pages":"6079101"},"PeriodicalIF":2.9,"publicationDate":"2018-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2018/6079101","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35864432","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-01-21eCollection Date: 2018-01-01DOI: 10.1155/2018/6727421
Seong-Hoon Yun, Sang-Heum Han, Joo-In Park
Peroxisome proliferator-activated receptor γ (PPARγ) is part of a nuclear receptor superfamily that regulates gene expression involved in cell differentiation, proliferation, immune/inflammation response, and lipid metabolism. PPARγ coactivator-1α (PGC-1α), initially identified as a PPARγ-interacting protein, is an important regulator of diverse metabolic pathways, such as oxidative metabolism and energy homeostasis. The role of PGC-1α in diabetes, neurodegeneration, and cardiovascular disease is particularly well known. PGC-1α is also now known to play important roles in cancer, independent of the role of PPARγ in cancer. Though many researchers have studied the expression and clinical implications of PPARγ and PGC-1α in cancer, there are still many controversies about the role of PPARγ and PGC-1α in cancer. This review examines and summarizes some recent data on the role and action mechanisms of PPARγ and PGC-1α in cancer, respectively, particularly the recent progress in understanding the role of PPARγ in several cancers since our review was published in 2012.
{"title":"Peroxisome Proliferator-Activated Receptor <i>γ</i> and PGC-1<i>α</i> in Cancer: Dual Actions as Tumor Promoter and Suppressor.","authors":"Seong-Hoon Yun, Sang-Heum Han, Joo-In Park","doi":"10.1155/2018/6727421","DOIUrl":"https://doi.org/10.1155/2018/6727421","url":null,"abstract":"<p><p>Peroxisome proliferator-activated receptor <i>γ</i> (PPAR<i>γ</i>) is part of a nuclear receptor superfamily that regulates gene expression involved in cell differentiation, proliferation, immune/inflammation response, and lipid metabolism. PPAR<i>γ</i> coactivator-1<i>α</i> (PGC-1<i>α</i>), initially identified as a PPAR<i>γ</i>-interacting protein, is an important regulator of diverse metabolic pathways, such as oxidative metabolism and energy homeostasis. The role of PGC-1<i>α</i> in diabetes, neurodegeneration, and cardiovascular disease is particularly well known. PGC-1<i>α</i> is also now known to play important roles in cancer, independent of the role of PPAR<i>γ</i> in cancer. Though many researchers have studied the expression and clinical implications of PPAR<i>γ</i> and PGC-1<i>α</i> in cancer, there are still many controversies about the role of PPAR<i>γ</i> and PGC-1<i>α</i> in cancer. This review examines and summarizes some recent data on the role and action mechanisms of PPAR<i>γ</i> and PGC-1<i>α</i> in cancer, respectively, particularly the recent progress in understanding the role of PPAR<i>γ</i> in several cancers since our review was published in 2012.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2018 ","pages":"6727421"},"PeriodicalIF":2.9,"publicationDate":"2018-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2018/6727421","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35961728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2018-01-15eCollection Date: 2018-01-01DOI: 10.1155/2018/6738703
Yajing Huo, Xuqing Wu, Jing Ding, Yang Geng, Weiwei Qiao, Anyan Ge, Cen Guo, Jianing Lv, Haifeng Bao, Wei Fan
Hyperhomocysteinemia, a risk factor for vascular disease, is associated with metabolic syndrome. Our study was aimed at exploring the effect of long-term hyperhomocysteinemia with metabolic disturbances on vascular remodeling. We also studied oxidative stress and expression of PPARγ in the coronary arteriole as a possible mechanism underlying vascular remodeling. Rats were treated with standard rodent chow (Control) or diet enriched in methionine (Met) for 48 weeks. Plasma homocysteine, blood glucose, serum lipids, malondialdehyde (MDA), superoxide dismutase (SOD), and nitric oxide (NO) levels were measured. Coronary arteriolar and carotid arterial remodeling was assessed by histomorphometric techniques and the expression of PPARγ in vessel wall was investigated. In Met group, an increase in the level of fasting blood glucose, serum triglyceride, total cholesterol, MDA, and NO, a decline in the serum SOD level, and increased collagen deposition in coronary and carotid arteries were found. Moreover, we detected decreased expression of PPARγ in the coronary arterioles in Met group. In summary, our study revealed metabolic disturbances in this model of long-term hyperhomocysteinemia together with vascular remodeling and suggested that impaired oxidative stress, endothelium dysfunction, and decreased PPARγ expression in the vessel wall could be underlying mechanisms.
高同型半胱氨酸血症是血管疾病的危险因素,与代谢综合征有关。我们的研究旨在探讨长期高同型半胱氨酸血症与代谢紊乱对血管重塑的影响。我们还研究了氧化应激和 PPARγ 在冠状动脉中的表达,以此作为血管重塑的可能机制。我们用标准啮齿动物饲料(对照组)或富含蛋氨酸(Met)的饮食对大鼠进行了为期 48 周的治疗。测量血浆同型半胱氨酸、血糖、血清脂质、丙二醛(MDA)、超氧化物歧化酶(SOD)和一氧化氮(NO)水平。通过组织形态计量学技术评估了冠状动脉和颈动脉的重塑情况,并调查了血管壁中 PPARγ 的表达情况。在 Met 组中,空腹血糖、血清甘油三酯、总胆固醇、MDA 和 NO 水平升高,血清 SOD 水平下降,冠状动脉和颈动脉中胶原沉积增加。此外,我们还检测到 Met 组冠状动脉中 PPARγ 的表达减少。总之,我们的研究揭示了长期高同型半胱氨酸血症模型中的代谢紊乱和血管重塑,并提示氧化应激受损、内皮功能障碍和血管壁中 PPARγ 表达减少可能是潜在的机制。
{"title":"Vascular Remodeling, Oxidative Stress, and Disrupted PPAR<i>γ</i> Expression in Rats of Long-Term Hyperhomocysteinemia with Metabolic Disturbance.","authors":"Yajing Huo, Xuqing Wu, Jing Ding, Yang Geng, Weiwei Qiao, Anyan Ge, Cen Guo, Jianing Lv, Haifeng Bao, Wei Fan","doi":"10.1155/2018/6738703","DOIUrl":"10.1155/2018/6738703","url":null,"abstract":"<p><p>Hyperhomocysteinemia, a risk factor for vascular disease, is associated with metabolic syndrome. Our study was aimed at exploring the effect of long-term hyperhomocysteinemia with metabolic disturbances on vascular remodeling. We also studied oxidative stress and expression of PPAR<i>γ</i> in the coronary arteriole as a possible mechanism underlying vascular remodeling. Rats were treated with standard rodent chow (Control) or diet enriched in methionine (Met) for 48 weeks. Plasma homocysteine, blood glucose, serum lipids, malondialdehyde (MDA), superoxide dismutase (SOD), and nitric oxide (NO) levels were measured. Coronary arteriolar and carotid arterial remodeling was assessed by histomorphometric techniques and the expression of PPAR<i>γ</i> in vessel wall was investigated. In Met group, an increase in the level of fasting blood glucose, serum triglyceride, total cholesterol, MDA, and NO, a decline in the serum SOD level, and increased collagen deposition in coronary and carotid arteries were found. Moreover, we detected decreased expression of PPAR<i>γ</i> in the coronary arterioles in Met group. In summary, our study revealed metabolic disturbances in this model of long-term hyperhomocysteinemia together with vascular remodeling and suggested that impaired oxidative stress, endothelium dysfunction, and decreased PPAR<i>γ</i> expression in the vessel wall could be underlying mechanisms.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2018 ","pages":"6738703"},"PeriodicalIF":3.5,"publicationDate":"2018-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35924883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Prasad P. Devarshi, Aarin D Jones, E. Taylor, B. Stefańska, T. Henagan
Pgc-1α and its various isoforms may play a role in determining skeletal muscle mitochondrial adaptations in response to diet. 8 wks of dietary supplementation with the flavonoid quercetin (Q) or red onion extract (ROE) in a high fat diet (HFD) ameliorates HFD-induced obesity and insulin resistance in C57BL/J mice while upregulating Pgc-1α and increasing skeletal muscle mitochondrial number and function. Here, mice were fed a low fat (LF), high fat (HF), high fat plus quercetin (HF + Q), or high fat plus red onion extract (HF + RO) diet for 9 wks and skeletal muscle Pgc-1α isoform expression and DNA methylation were determined. Quantification of various Pgc-1α isoforms, including isoforms Pgc-1α-a, Pgc-1α-b, Pgc-1α-c, Pgc-1α4, total NT-Pgc-1α, and FL-Pgc-1α, showed that only total NT-Pgc-1α expression was increased in LF, HF + Q, and HF + RO compared to HF. Furthermore, Q supplementation decreased Pgc-1α-a expression compared to LF and HF, and ROE decreased Pgc-1α-a expression compared to LF. FL-Pgc-1α was decreased in HF + Q and HF + RO compared to LF and HF. HF exhibited hypermethylation at the −260 nucleotide (nt) in the Pgc-1α promoter. Q and ROE prevented HFD-induced hypermethylation. −260 nt methylation levels were associated with NT-Pgc-1α expression only. Pgc-1α isoform expression may be epigenetically regulated by Q and ROE through DNA methylation.
{"title":"Quercetin and Quercetin-Rich Red Onion Extract Alter Pgc-1α Promoter Methylation and Splice Variant Expression","authors":"Prasad P. Devarshi, Aarin D Jones, E. Taylor, B. Stefańska, T. Henagan","doi":"10.1155/2017/3235693","DOIUrl":"https://doi.org/10.1155/2017/3235693","url":null,"abstract":"Pgc-1α and its various isoforms may play a role in determining skeletal muscle mitochondrial adaptations in response to diet. 8 wks of dietary supplementation with the flavonoid quercetin (Q) or red onion extract (ROE) in a high fat diet (HFD) ameliorates HFD-induced obesity and insulin resistance in C57BL/J mice while upregulating Pgc-1α and increasing skeletal muscle mitochondrial number and function. Here, mice were fed a low fat (LF), high fat (HF), high fat plus quercetin (HF + Q), or high fat plus red onion extract (HF + RO) diet for 9 wks and skeletal muscle Pgc-1α isoform expression and DNA methylation were determined. Quantification of various Pgc-1α isoforms, including isoforms Pgc-1α-a, Pgc-1α-b, Pgc-1α-c, Pgc-1α4, total NT-Pgc-1α, and FL-Pgc-1α, showed that only total NT-Pgc-1α expression was increased in LF, HF + Q, and HF + RO compared to HF. Furthermore, Q supplementation decreased Pgc-1α-a expression compared to LF and HF, and ROE decreased Pgc-1α-a expression compared to LF. FL-Pgc-1α was decreased in HF + Q and HF + RO compared to LF and HF. HF exhibited hypermethylation at the −260 nucleotide (nt) in the Pgc-1α promoter. Q and ROE prevented HFD-induced hypermethylation. −260 nt methylation levels were associated with NT-Pgc-1α expression only. Pgc-1α isoform expression may be epigenetically regulated by Q and ROE through DNA methylation.","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2017-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2017/3235693","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48293405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-dependent nuclear receptors, which control the transcription of genes involved in energy homeostasis and inflammation and cell proliferation/differentiation. Alterations of PPARs' expression and/or activity are commonly associated with metabolic disorders occurring with obesity, type 2 diabetes, and fatty liver disease, as well as with inflammation and cancer. Emerging evidence now indicates that microRNAs (miRNAs), a family of small noncoding RNAs, which fine-tune gene expression, play a significant role in the pathophysiological mechanisms regulating the expression and activity of PPARs. Herein, the regulation of PPARs by miRNAs is reviewed in the context of metabolic disorders, inflammation, and cancer. The reciprocal control of miRNAs expression by PPARs, as well as the therapeutic potential of modulating PPAR expression/activity by pharmacological compounds targeting miRNA, is also discussed.
{"title":"MicroRNAs-Dependent Regulation of PPARs in Metabolic Diseases and Cancers","authors":"Dorothea Portius, Cyril Sobolewski, Michelangelo Foti","doi":"10.1155/2017/7058424","DOIUrl":"https://doi.org/10.1155/2017/7058424","url":null,"abstract":"Peroxisome proliferator-activated receptors (PPARs) are a family of ligand-dependent nuclear receptors, which control the transcription of genes involved in energy homeostasis and inflammation and cell proliferation/differentiation. Alterations of PPARs' expression and/or activity are commonly associated with metabolic disorders occurring with obesity, type 2 diabetes, and fatty liver disease, as well as with inflammation and cancer. Emerging evidence now indicates that microRNAs (miRNAs), a family of small noncoding RNAs, which fine-tune gene expression, play a significant role in the pathophysiological mechanisms regulating the expression and activity of PPARs. Herein, the regulation of PPARs by miRNAs is reviewed in the context of metabolic disorders, inflammation, and cancer. The reciprocal control of miRNAs expression by PPARs, as well as the therapeutic potential of modulating PPAR expression/activity by pharmacological compounds targeting miRNA, is also discussed.","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":" ","pages":""},"PeriodicalIF":2.9,"publicationDate":"2017-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2017/7058424","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46389599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background. Peroxisome proliferator-activated receptor-α (PPAR-α) is closely associated with the development of cardiac hypertrophy. Previous studies have indicated that bezafibrate (BZA), a PPAR-α agonist, could attenuate insulin resistance and obesity. This study was designed to determine whether BZA could protect against pressure overload-induced cardiac hypertrophy. Methods. Mice were orally given BZA (100 mg/kg) for 7 weeks beginning 1 week after aortic banding (AB) surgery. Cardiac hypertrophy was assessed based on echocardiographic, histological, and molecular aspects. Moreover, neonatal rat ventricular cardiomyocytes (NRVMs) were used to investigate the effects of BZA on the cardiomyocyte hypertrophic response in vitro. Results. Our study demonstrated that BZA could alleviate cardiac hypertrophy and fibrosis in mice subjected to AB surgery. BZA treatment also reduced the phosphorylation of protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β) and mitogen-activated protein kinases (MAPKs). BZA suppressed phenylephrine- (PE-) induced hypertrophy of cardiomyocyte in vitro. The protective effects of BZA were abolished by the treatment of the PPAR-α antagonist in vitro. Conclusions. BZA could attenuate pressure overload-induced cardiac hypertrophy and fibrosis.
{"title":"Bezafibrate Attenuates Pressure Overload-Induced Cardiac Hypertrophy and Fibrosis","authors":"Si-Chi Xu, Zhen-Guo Ma, Wen-ying Wei, Yu-Pei Yuan, Q. Tang","doi":"10.1155/2017/5789714","DOIUrl":"https://doi.org/10.1155/2017/5789714","url":null,"abstract":"Background. Peroxisome proliferator-activated receptor-α (PPAR-α) is closely associated with the development of cardiac hypertrophy. Previous studies have indicated that bezafibrate (BZA), a PPAR-α agonist, could attenuate insulin resistance and obesity. This study was designed to determine whether BZA could protect against pressure overload-induced cardiac hypertrophy. Methods. Mice were orally given BZA (100 mg/kg) for 7 weeks beginning 1 week after aortic banding (AB) surgery. Cardiac hypertrophy was assessed based on echocardiographic, histological, and molecular aspects. Moreover, neonatal rat ventricular cardiomyocytes (NRVMs) were used to investigate the effects of BZA on the cardiomyocyte hypertrophic response in vitro. Results. Our study demonstrated that BZA could alleviate cardiac hypertrophy and fibrosis in mice subjected to AB surgery. BZA treatment also reduced the phosphorylation of protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β) and mitogen-activated protein kinases (MAPKs). BZA suppressed phenylephrine- (PE-) induced hypertrophy of cardiomyocyte in vitro. The protective effects of BZA were abolished by the treatment of the PPAR-α antagonist in vitro. Conclusions. BZA could attenuate pressure overload-induced cardiac hypertrophy and fibrosis.","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2017 1","pages":""},"PeriodicalIF":2.9,"publicationDate":"2017-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2017/5789714","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"64688948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-01-01Epub Date: 2017-05-30DOI: 10.1155/2017/2647129
Ya-Ge Jin, Yuan Yuan, Qing-Qing Wu, Ning Zhang, Di Fan, Yan Che, Zhao-Peng Wang, Yang Xiao, Sha-Sha Wang, Qi-Zhu Tang
Background: Puerarin is a kind of flavonoids and is extracted from Chinese herb Kudzu root. Puerarin is widely used as an adjuvant therapy in Chinese clinics. But little is known about its effects on regulating cardiac fibrosis.
Methods: Mice were subjected to transverse aorta constriction (TAC) for 8 weeks; meanwhile puerarin was given 1 week after TAC. Cardiac fibrosis was assessed by pathological staining. The mRNA and protein changes of CD31 and vimentin in both animal and human umbilical vein endothelial cells (HUVECs) models were detected. Immunofluorescence colocalization of CD31 and vimentin and scratch test were carried out to examine TGF-β1-induced changes in HUVECs. The agonist and antagonist of peroxisome proliferator-activated receptor-γ (PPAR-γ) were used to explore the underlying mechanism.
Results: Puerarin mitigated TAC-induced cardiac fibrosis, accompanied with suppressed endothelial-to-mesenchymal transition (EndMT). The consistent results were achieved in HUVECs model. TGF-β1/Smad2 signaling pathway was blunted and PPAR-γ expression was upregulated in puerarin-treated mice and HUVECs. Pioglitazone could reproduce the protective effect in HUVECs, while GW9662 reversed this effect imposed by puerarin.
Conclusion: Puerarin protected against TAC-induced cardiac fibrosis, and this protective effect may be attributed to the upregulation of PPAR-γ and the inhibition of TGF-β1/Smad2-mediated EndMT.
{"title":"Puerarin Protects against Cardiac Fibrosis Associated with the Inhibition of TGF-<i>β</i>1/Smad2-Mediated Endothelial-to-Mesenchymal Transition.","authors":"Ya-Ge Jin, Yuan Yuan, Qing-Qing Wu, Ning Zhang, Di Fan, Yan Che, Zhao-Peng Wang, Yang Xiao, Sha-Sha Wang, Qi-Zhu Tang","doi":"10.1155/2017/2647129","DOIUrl":"https://doi.org/10.1155/2017/2647129","url":null,"abstract":"<p><strong>Background: </strong>Puerarin is a kind of flavonoids and is extracted from Chinese herb Kudzu root. Puerarin is widely used as an adjuvant therapy in Chinese clinics. But little is known about its effects on regulating cardiac fibrosis.</p><p><strong>Methods: </strong>Mice were subjected to transverse aorta constriction (TAC) for 8 weeks; meanwhile puerarin was given 1 week after TAC. Cardiac fibrosis was assessed by pathological staining. The mRNA and protein changes of CD31 and vimentin in both animal and human umbilical vein endothelial cells (HUVECs) models were detected. Immunofluorescence colocalization of CD31 and vimentin and scratch test were carried out to examine TGF-<i>β</i>1-induced changes in HUVECs. The agonist and antagonist of peroxisome proliferator-activated receptor-<i>γ</i> (PPAR-<i>γ</i>) were used to explore the underlying mechanism.</p><p><strong>Results: </strong>Puerarin mitigated TAC-induced cardiac fibrosis, accompanied with suppressed endothelial-to-mesenchymal transition (EndMT). The consistent results were achieved in HUVECs model. TGF-<i>β</i>1/Smad2 signaling pathway was blunted and PPAR-<i>γ</i> expression was upregulated in puerarin-treated mice and HUVECs. Pioglitazone could reproduce the protective effect in HUVECs, while GW9662 reversed this effect imposed by puerarin.</p><p><strong>Conclusion: </strong>Puerarin protected against TAC-induced cardiac fibrosis, and this protective effect may be attributed to the upregulation of PPAR-<i>γ</i> and the inhibition of TGF-<i>β</i>1/Smad2-mediated EndMT.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2017 ","pages":"2647129"},"PeriodicalIF":2.9,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2017/2647129","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"35108214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2017-01-01Epub Date: 2017-03-13DOI: 10.1155/2017/8048720
Yong-Jik Lee, Yoo-Na Jang, Yoon-Mi Han, Hyun-Min Kim, Jong-Min Jeong, Hong Seog Seo
To investigate the effects of fimasartan on nonalcoholic fatty liver disease in hyperlipidemic and hypertensive conditions, the levels of biomarkers related to fatty acid metabolism were determined in HepG2 and differentiated 3T3-L1 cells treated by high fatty acid and liver and visceral fat tissue samples of spontaneously hypertensive rats (SHRs) given high-fat diet. In HepG2 cells and liver tissues, fimasartan was shown to increase the protein levels of peroxisome proliferator-activated receptor delta (PPARδ), phosphorylated 5' adenosine monophosphate-activated protein kinase (p-AMPK), phosphorylated acetyl-CoA carboxylase (p-ACC), malonyl-CoA decarboxylase (MCD), medium chain acyl-CoA dehydrogenase (MCAD), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), and it led to a decrease in the protein levels of 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSDH1), fatty acid synthase (FAS), and tumor necrosis factor-alpha (TNF-α). Fimasartan decreased lipid contents in HepG2 and differentiated 3T3-L1 cells and liver tissues. In addition, fimasartan increased the adiponectin level in visceral fat tissues. The antiadipogenic effects of fimasartan were offset by PPARδ antagonist (GSK0660). Consequently, fimasartan ameliorates nonalcoholic fatty liver disease mainly through the activation of oxidative metabolism represented by PPARδ-AMPK-PGC-1α pathway.
{"title":"Fimasartan Ameliorates Nonalcoholic Fatty Liver Disease through PPAR<i>δ</i> Regulation in Hyperlipidemic and Hypertensive Conditions.","authors":"Yong-Jik Lee, Yoo-Na Jang, Yoon-Mi Han, Hyun-Min Kim, Jong-Min Jeong, Hong Seog Seo","doi":"10.1155/2017/8048720","DOIUrl":"https://doi.org/10.1155/2017/8048720","url":null,"abstract":"<p><p>To investigate the effects of fimasartan on nonalcoholic fatty liver disease in hyperlipidemic and hypertensive conditions, the levels of biomarkers related to fatty acid metabolism were determined in HepG2 and differentiated 3T3-L1 cells treated by high fatty acid and liver and visceral fat tissue samples of spontaneously hypertensive rats (SHRs) given high-fat diet. In HepG2 cells and liver tissues, fimasartan was shown to increase the protein levels of peroxisome proliferator-activated receptor delta (PPAR<i>δ</i>), phosphorylated 5' adenosine monophosphate-activated protein kinase (p-AMPK), phosphorylated acetyl-CoA carboxylase (p-ACC), malonyl-CoA decarboxylase (MCD), medium chain acyl-CoA dehydrogenase (MCAD), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1<i>α</i>), and it led to a decrease in the protein levels of 11 beta-hydroxysteroid dehydrogenase 1 (11<i>β</i>-HSDH1), fatty acid synthase (FAS), and tumor necrosis factor-alpha (TNF-<i>α</i>). Fimasartan decreased lipid contents in HepG2 and differentiated 3T3-L1 cells and liver tissues. In addition, fimasartan increased the adiponectin level in visceral fat tissues. The antiadipogenic effects of fimasartan were offset by PPAR<i>δ</i> antagonist (GSK0660). Consequently, fimasartan ameliorates nonalcoholic fatty liver disease mainly through the activation of oxidative metabolism represented by PPAR<i>δ</i>-AMPK-PGC-1<i>α</i> pathway.</p>","PeriodicalId":20439,"journal":{"name":"PPAR Research","volume":"2017 ","pages":"8048720"},"PeriodicalIF":2.9,"publicationDate":"2017-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2017/8048720","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34894572","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}