scholarly journals PGC1/PPAR drive cardiomyocyte maturation at single cell level via YAP1 and SF3B2

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Sean A. Murphy ◽  
Matthew Miyamoto ◽  
Anaïs Kervadec ◽  
Suraj Kannan ◽  
Emmanouil Tampakakis ◽  
...  
Keyword(s):  
Single Cell ◽  
Peroxisome Proliferator ◽  
Cell Level ◽  
Peroxisome Proliferator Activated Receptor ◽  
Functional Changes ◽  
Particle Sorting ◽  
Gene Regulatory ◽  
Size Heterogeneity ◽  
Key Aspects

AbstractCardiomyocytes undergo significant structural and functional changes after birth, and these fundamental processes are essential for the heart to pump blood to the growing body. However, due to the challenges of isolating single postnatal/adult myocytes, how individual newborn cardiomyocytes acquire multiple aspects of the mature phenotype remains poorly understood. Here we implement large-particle sorting and analyze single myocytes from neonatal to adult hearts. Early myocytes exhibit wide-ranging transcriptomic and size heterogeneity that is maintained until adulthood with a continuous transcriptomic shift. Gene regulatory network analysis followed by mosaic gene deletion reveals that peroxisome proliferator-activated receptor coactivator-1 signaling, which is active in vivo but inactive in pluripotent stem cell-derived cardiomyocytes, mediates the shift. This signaling simultaneously regulates key aspects of cardiomyocyte maturation through previously unrecognized proteins, including YAP1 and SF3B2. Our study provides a single-cell roadmap of heterogeneous transitions coupled to cellular features and identifies a multifaceted regulator controlling cardiomyocyte maturation.

scholarly journals PGC1/PPAR Drive Cardiomyocyte Maturation through Regulation of Yap1 and SF3B2

2020 ◽  
Author(s):  
Sean Murphy ◽  
Matthew Miyamoto ◽  
Anais Kervadec ◽  
Suraj Kannan ◽  
Emmanouil Tampakakis ◽  
...  
Keyword(s):  
Stem Cell ◽  
Single Cell ◽  
Pluripotent Stem Cell ◽  
Mitochondrial Activity ◽  
Peroxisome Proliferator ◽  
Cardiac Muscle Cells ◽  
Peroxisome Proliferator Activated Receptor ◽  
Functional Changes ◽  
Key Aspects

Cardiomyocytes undergo significant levels of structural and functional changes after birth—fundamental processes essential for the heart to produce the volume and contractility to pump blood to the growing body. However, due to the challenges in isolating single postnatal/adult myocytes, how individual newborn cardiomyocytes acquire multiple aspects of mature phenotypes remains poorly understood. Here we implemented large-particle sorting and analyzed single myocytes from neonatal to adult hearts. Early myocytes exhibited a wide-ranging transcriptomic and size heterogeneity, maintained until adulthood with a continuous transcriptomic shift. Gene regulatory network analysis followed by mosaic gene deletion revealed that peroxisome proliferator-activated receptor coactivator-1 signaling—activated in vivo but inactive in pluripotent stem cell-derived cardiomyocytes—mediates the shift. The signaling regulated key aspects of cardiomyocyte maturation simultaneously through previously unrecognized regulators, including Yap1 and SF3B2. Our study provides a single-cell roadmap of heterogeneous transitions coupled to cellular features and unveils a multifaceted regulator controlling cardiomyocyte maturation.Significance StatementHow the individual single myocytes achieve full maturity remains a ‘black box’, largely due to the challenges with the isolation of single mature myocytes. Understanding this process is particularly important as the immaturity and early developmental arrest of pluripotent stem cell-derived myocytes has emerged a major concern in the field. Here we present the first study of high-quality single-cell transcriptomic analysis of cardiac muscle cells from neonatal to adult hearts. We identify a central transcription factor and its novel targets that control key aspects of myocyte maturation, including cellular hypertrophy, contractility, and mitochondrial activity.

scholarly journals IRF1-mediated downregulation of PGC1α contributes to cardiorenal syndrome type 4

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Yinghui Huang ◽  
Shaobo Wang ◽  
Jie Zhou ◽  
Yong Liu ◽  
Changhong Du ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Cardiorenal Syndrome ◽  
Peroxisome Proliferator ◽  
Syndrome Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Myocardial Energy Metabolism ◽  
Functional Changes ◽  
Myocardial Mitochondria

Abstract Cardiorenal syndrome type 4 (CRS4) is a common complication of chronic kidney disease (CKD), but the pathogenic mechanisms remain elusive. Here we report that morphological and functional changes in myocardial mitochondria are observed in CKD mice, especially decreases in oxidative phosphorylation and fatty acid metabolism. High phosphate (HP), a hallmark of CKD, contributes to myocardial energy metabolism dysfunction by downregulating peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α). Furthermore, the transcriptional factor interferon regulatory factor 1 (IRF1) is revealed as the key molecule upregulated by HP through histone H3K9 acetylation, and responsible for the HP-mediated transcriptional inhibition of PGC1α by directly binding to its promoter region. Conversely, restoration of PGC1α expression or genetic knockdown of IRF1 significantly attenuates HP-induced alterations in vitro and in vivo. These findings demonstrate that IRF1-PGC1α axis-mediated myocardial energy metabolism remodeling plays a crucial role in the pathogenesis of CRS4.

scholarly journals Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
KyeongJin Kim ◽  
Jin Ku Kang ◽  
Young Hoon Jung ◽  
Sang Bae Lee ◽  
Raffaela Rametta ◽  
...  
Keyword(s):  
Fatty Liver ◽  
Whole Body ◽  
Acid Oxidation ◽  
Chow Diet ◽  
Peroxisome Proliferator ◽  
Obese Mice ◽  
Ph Domain ◽  
Peroxisome Proliferator Activated Receptor

AbstractIncreased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

scholarly journals The lipid-lowering drug fenofibrate combined with si-HOTAIR can effectively inhibit the proliferation of gliomas

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Wei Zhu ◽  
Hongyang Zhao ◽  
Fenfen Xu ◽  
Bin Huang ◽  
Xiaojing Dai ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Glioma Cells ◽  
Lipid Lowering ◽  
Fibric Acid Derivative ◽  
Peroxisome Proliferator ◽  
Glioma Invasion ◽  
Peroxisome Proliferator Activated Receptor ◽  
Lncrna Hotair

Abstract Background Fenofibrate is a fibric acid derivative known to have a lipid-lowering effect. Although fenofibrate-induced peroxisome proliferator-activated receptor alpha (PPARα) transcription activation has been shown to play an important role in the malignant progression of gliomas, the underlying mechanisms are poorly understood. Methods In this study, we analyzed TCGA database and found that there was a significant negative correlation between the long noncoding RNA (lncRNA) HOTAIR and PPARα. Then, we explored the molecular mechanism by which lncRNA HOTAIR regulates PPARα in cell lines in vitro and in a nude mouse glioma model in vivo and explored the effect of the combined application of HOTAIR knockdown and fenofibrate treatment on glioma invasion. Results For the first time, it was shown that after knockdown of the expression of HOTAIR in gliomas, the expression of PPARα was significantly upregulated, and the invasion and proliferation ability of gliomas were obviously inhibited. Then, glioma cells were treated with both the PPARα agonist fenofibrate and si-HOTAIR, and the results showed that the proliferation and invasion of glioma cells were significantly inhibited. Conclusions Our results suggest that HOTAIR can negatively regulate the expression of PPARα and that the combination of fenofibrate and si-HOTAIR treatment can significantly inhibit the progression of gliomas. This introduces new ideas for the treatment of gliomas.

scholarly journals The Novel Role of PGC1α in Bone Metabolism

2021 ◽  
Vol 22 (9) ◽  
pp. 4670
Author(s):  
Cinzia Buccoliero ◽  
Manuela Dicarlo ◽  
Patrizia Pignataro ◽  
Francesco Gaccione ◽  
Silvia Colucci ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
Osteoblastic Differentiation ◽  
In Vivo Studies ◽  
Peroxisome Proliferator ◽  
Sirtuin 3 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Increased Risk

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a protein that promotes transcription of numerous genes, particularly those responsible for the regulation of mitochondrial biogenesis. Evidence for a key role of PGC1α in bone metabolism is very recent. In vivo studies showed that PGC1α deletion negatively affects cortical thickness, trabecular organization and resistance to flexion, resulting in increased risk of fracture. Furthermore, in a mouse model of bone disease, PGC1α activation stimulates osteoblastic gene expression and inhibits atrogene transcription. PGC1α overexpression positively affects the activity of Sirtuin 3, a mitochondrial nicotinammide adenina dinucleotide (NAD)-dependent deacetylase, on osteoblastic differentiation. In vitro, PGC1α overexpression prevents the reduction of mitochondrial density, membrane potential and alkaline phosphatase activity caused by Sirtuin 3 knockdown in osteoblasts. Moreover, PGC1α influences the commitment of skeletal stem cells towards an osteogenic lineage, while negatively affects marrow adipose tissue accumulation. In this review, we will focus on recent findings about PGC1α action on bone metabolism, in vivo and in vitro, and in pathologies that cause bone loss, such as osteoporosis and type 2 diabetes.

scholarly journals Protein Kinase A/CREB Signaling Prevents Adriamycin-Induced Podocyte Apoptosis via Upregulation of Mitochondrial Respiratory Chain Complexes

2017 ◽  
Vol 38 (1) ◽  
Author(s):  
Kewei Xie ◽  
Mingli Zhu ◽  
Peng Xiang ◽  
Xiaohuan Chen ◽  
Ayijiaken Kasimumali ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinase A ◽  
Respiratory Chain ◽  
Mitochondrial Respiratory Chain ◽  
Peroxisome Proliferator ◽  
Respiratory Chain Complexes ◽  
Peroxisome Proliferator Activated Receptor ◽  
Kinase A ◽  
Mitochondrial Respiratory

ABSTRACT Previous work showed that the activation of protein kinase A (PKA) signaling promoted mitochondrial fusion and prevented podocyte apoptosis. The cAMP response element binding protein (CREB) is the main downstream transcription factor of PKA signaling. Here we show that the PKA agonist 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate–cyclic AMP (pCPT-cAMP) prevented the production of adriamycin (ADR)-induced reactive oxygen species and apoptosis in podocytes, which were inhibited by CREB RNA interference (RNAi). The activation of PKA enhanced mitochondrial function and prevented the ADR-induced decrease of mitochondrial respiratory chain complex I subunits, NADH-ubiquinone oxidoreductase complex (ND) 1/3/4 genes, and protein expression. Inhibition of CREB expression alleviated pCPT-cAMP-induced ND3, but not the recovery of ND1/4 protein, in ADR-treated podocytes. In addition, CREB RNAi blocked the pCPT-cAMP-induced increase in ATP and the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1-α). The chromatin immunoprecipitation assay showed enrichment of CREB on PGC1-α and ND3 promoters, suggesting that these promoters are CREB targets. In vivo, both an endogenous cAMP activator (isoproterenol) and pCPT-cAMP decreased the albumin/creatinine ratio in mice with ADR nephropathy, reduced glomerular oxidative stress, and retained Wilm's tumor suppressor gene 1 (WT-1)-positive cells in glomeruli. We conclude that the upregulation of mitochondrial respiratory chain proteins played a partial role in the protection of PKA/CREB signaling.

scholarly journals Activation of Peroxisome Proliferator-Activated Receptor γ Does Not Inhibit IL-6 or TNF-α Responses of Macrophages to Lipopolysaccharide In Vitro or In Vivo

2000 ◽  
Vol 164 (2) ◽  
pp. 1046-1054 ◽  
Author(s):  
Rolf Thieringer ◽  
Judy E. Fenyk-Melody ◽  
Cheryl B. Le Grand ◽  
Beverly A. Shelton ◽  
Patricia A. Detmers ◽  
...  
Keyword(s):  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Tnf Α

scholarly journals Opposing Roles of Peroxisome Proliferator-activated Receptor α and Growth Hormone in the Regulation of CYP4A11 Expression in a Transgenic Mouse Model

2009 ◽  
Vol 284 (24) ◽  
pp. 16541-16552 ◽  
Author(s):  
Üzen Savas ◽  
Daniel E. W. Machemer ◽  
Mei-Hui Hsu ◽  
Pryce Gaynor ◽  
Jerome M. Lasker ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Hormone ◽  
Transgenic Mice ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Peroxisome Proliferator ◽  
Sexually Dimorphic ◽  
Peroxisome Proliferator Activated Receptor ◽  
Liver And Kidney

CYP4A11 transgenic mice (CYP4A11 Tg) were generated to examine in vivo regulation of the human CYP4A11 gene. Expression of CYP4A11 in mice yields liver and kidney P450 4A11 levels similar to those found in the corresponding human tissues and leads to an increased microsomal capacity for ω-hydroxylation of lauric acid. Fasted CYP4A11 Tg mice exhibit 2–3-fold increases in hepatic CYP4A11 mRNA and protein, and this response is absent in peroxisome proliferator-activated receptor α (PPARα) null mice. Dietary administration of either of the PPARα agonists, fenofibrate or clofibric acid, increases hepatic and renal CYP4A11 levels by 2–3-fold, and these responses were also abrogated in PPARα null mice. Basal liver CYP4A11 levels are reduced differentially in PPARα−/− females (>95%) and males (<50%) compared with PPARα−/+ mice. Quantitative and temporal differences in growth hormone secretion are known to alter hepatic lipid metabolism and to underlie sexually dimorphic gene expression, respectively. Continuous infusion of low levels of growth hormone reduced CYP4A11 expression by 50% in PPARα-proficient male and female transgenic mice. A larger decrease was observed for the expression of CYP4A11 in PPARα−/− CYP4A11 Tg male mice to levels similar to that of female PPARα-deficient mice. These results suggest that PPARα contributes to the maintenance of basal CYP4A11 expression and mediates CYP4A11 induction in response to fibrates or fasting. In contrast, increased exposure to growth hormone down-regulates CYP4A11 expression in liver.

Abstract 12555: The Dual PPAR-α/γ Agonist Aleglitazar Enhances Arteriogenesis, Angiogenesis and Endothelial Function

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Christian Werner ◽  
Stephan H Schirmer ◽  
Valerie Pavlickova ◽  
Michael Böhm ◽  
Ulrich Laufs
Keyword(s):  
Endothelial Function ◽  
Vascular Function ◽  
Daily Injection ◽  
Peroxisome Proliferator ◽  
Fluorescent Microspheres ◽  
Artery Ligation ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
And Function

Objective: Peroxisome proliferator-activated receptor (PPAR)-α and -γ agonists modify lipid and glucose metabolism. The aim of the study was to characterize the effects of the dual PPAR-α/γ agonist aleglitazar on endothelial function, neoangiogenesis and arteriogenesis in mice and on human endothelial progenitor cells (EPC). Methods and Results: Male C57Bl/6 wild-type (WT, normal chow) and apolipoprotein E-deficient (apoE-/-) mice on Western-type diet (WTD) were treated with aleglitazar (10 mg/kg i.p.) or vehicle by daily injection. Hindlimb ischemia was induced by right femoral artery ligation (FAL). ApoE-/- mice on WTD treated with aleglitazar before FAL were characterized by an improvement of endothelial-dependent laser Doppler perfusion (right/left foot ratio 0.40±0.03) 1 week after FAL compared to controls (R/L foot ratio 0.24±0.01; p<0.001). Collateral-dependent perfusion measured under conditions of maximal vasodilatation 1 week after FAL using fluorescent microspheres was impaired in apoE-/- on WTD compared to WT mice (R/L leg ratio in WT 78±13 vs. apoE-/- 56±6; p<0.001) and was normalized by aleglitazar treatment. Neoangiogenesis was measured in-vivo by subcutaneously implanting discs covered with cell-impermeable filters. The vascularized area of the discs was quantified after 14 days by perfusion of the animals with space-filling fluorescent microspheres. Aleglitazar increased neoangiogenesis in WT mice by 178±18% compared to vehicle (p<0.05). Endothelium-dependent relaxation of aortic rings was impaired in apoE-/- mice on WTD for 6 weeks (relaxation to 52±5% of max. contraction) compared to WT animals (relaxation to 18±5% of max. contraction) (p<0.001). Aleglitazar treatment improved endothelial function (relaxation to 39±5% of max. contraction; p<0.05). In parallel, number and function of EPC were improved in mice. Studies in human EPC showed that 1) aleglitazar’s effects were mediated by both PPAR-α and -γ signalling and Akt and 2) migration and colony forming units were up-regulated by aleglitazar in cultivated EPC from CAD patients. Conclusion: The study provides evidence for beneficial effects of the dual PPAR-α/γ agonist aleglitazar on vascular function in addition to or mediated by its metabolic actions.

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