scholarly journals Zinc finger protein 407 overexpression upregulates PPAR target gene expression and improves glucose homeostasis in mice

2016 ◽  
Vol 311 (5) ◽  
pp. E869-E880 ◽  
Author(s):  
Alyssa Charrier ◽  
Li Wang ◽  
Erin J. Stephenson ◽  
Siddharth V. Ghanta ◽  
Chih-wei Ko ◽  
...  
Keyword(s):  
Metabolic Disease ◽  
Glucose Homeostasis ◽  
Target Genes ◽  
Glucose Transporter ◽  
Zinc Finger Protein ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Expression Of Genes ◽  
Transgenic Mouse Strain

The peroxisome proliferator-activated receptor (PPAR) family of nuclear receptors is central to the pathophysiology and treatment of metabolic disease through the receptors' ability to regulate the expression of genes involved in glucose homeostasis, adipogenesis, and lipid metabolism. However, the mechanism by which PPAR is regulated remains incompletely understood. We generated a transgenic mouse strain (ZFP-TG) that overexpressed Zfp407 primarily in muscle and heart. Transcriptome analysis by RNA-Seq identified 1,300 differentially expressed genes in the muscle of ZFP-TG mice, among which PPAR target genes were significantly enriched. Among the physiologically important PPARγ target genes, Glucose transporter (Glut)-4 mRNA and protein levels were increased in heart and muscle. The increase in Glut4 and other transcriptional effects of Zfp407 overexpression together decreased body weight and lowered plasma glucose, insulin, and HOMA-IR scores relative to control littermates. When placed on high-fat diet, ZFP-TG mice remained more glucose tolerant than their wild-type counterparts. Cell-based assays demonstrated that Zfp407 synergistically increased the transcriptional activity of all PPAR subtypes, PPARα, PPARγ, and PPARδ. The increased PPAR activity was not associated with increased PPAR mRNA or protein levels, suggesting that Zfp407 posttranslationally regulates PPAR activity. Collectively, these results demonstrate that Zfp407 overexpression improved glucose homeostasis. Thus, Zfp407 represents a new drug target for treating metabolic disease.

Insulin resistance: cross-talk between adipose tissue and skeletal muscle, through free fatty acids, liver X receptor, and peroxisome proliferator-activated receptor-α signaling

2013 ◽  
Vol 15 (3) ◽  
Author(s):  
Ann Louise Olson
Keyword(s):  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Glucose Homeostasis ◽  
Glucose Transporter ◽  
Control Point ◽  
Nuclear Hormone Receptor ◽  
Whole Body ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

AbstractSkeletal muscle and adipose tissue play a major role in the regulation of whole-body glucose homeostasis. Much of the coordinated regulation of whole-body glucose homeostasis results from the regulation of lipid storage and release by adipose tissue and efficient switching between glucose oxidation and fatty acid oxidation in skeletal muscle. A control point for these biochemical actions center around the regulation of the insulin responsive glucose transporter, GLUT4. This review examines the regulation of GLUT4 in adipose tissue and skeletal muscle, in the context of the steroid nuclear hormone receptor signaling.

scholarly journals Central leptin regulates heart lipid content by selectively increasing PPAR β/δ expression

2018 ◽  
Vol 236 (1) ◽  
pp. 43-56 ◽  
Author(s):  
Cristina Mora ◽  
Cristina Pintado ◽  
Blanca Rubio ◽  
Lorena Mazuecos ◽  
Virginia López ◽  
...  
Keyword(s):  
Target Genes ◽  
Cardiac Tissue ◽  
Cardiac Metabolism ◽  
Pyruvate Dehydrogenase Kinase ◽  
Hormone Sensitive Lipase ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Expression Of Genes ◽  
Gene And Protein Expression ◽  
Tag Accumulation

The role of central leptin in regulating the heart from lipid accumulation in lean leptin-sensitive animals has not been fully elucidated. Herein, we investigated the effects of central leptin infusion on the expression of genes involved in cardiac metabolism and its role in the control of myocardial triacylglyceride (TAG) accumulation in adult Wistar rats. Intracerebroventricular (icv) leptin infusion (0.2 µg/day) for 7 days markedly decreased TAG levels in cardiac tissue. Remarkably, the cardiac anti-steatotic effects of central leptin were associated with the selective upregulation of gene and protein expression of peroxisome proliferator-activated receptor β/δ (PPARβ/δ, encoded by Pparb/d) and their target genes, adipose triglyceride lipase (encoded by Pnpla2, herefater referred to as Atgl), hormone sensitive lipase (encoded by Lipe, herefater referred to as Hsl), pyruvate dehydrogenase kinase 4 (Pdk4) and acyl CoA oxidase 1 (Acox1), involved in myocardial intracellular lipolysis and mitochondrial/peroxisomal fatty acid utilization. Besides, central leptin decreased the expression of stearoyl-CoA deaturase 1 (Scd1) and diacylglycerol acyltransferase 1 (Dgat1) involved in TAG synthesis and increased the CPT-1 independent palmitate oxidation, as an index of peroxisomal β-oxidation. Finally, the pharmacological inhibition of PPARβ/δ decreased the effects on gene expression and cardiac TAG content induced by leptin. These results indicate that leptin, acting at central level, regulates selectively the cardiac expression of PPARβ/δ, contributing in this way to regulate the cardiac TAG accumulation in rats, independently of its effects on body weight.

scholarly journals Upregulation of Genes Involved in Cardiac Metabolism Enhances Myocardial Resistance to Ischemia/Reperfusion in the Rat Heart

2013 ◽  
pp. S151-S163 ◽  
Author(s):  
T. RAVINGEROVÁ ◽  
S. ČARNICKÁ ◽  
V. LEDVÉNYIOVÁ ◽  
E. BARLAKA ◽  
E. GALATOU ◽  
...  
Keyword(s):  
Rat Heart ◽  
Target Genes ◽  
Glucose Transporter ◽  
Ischemia Reperfusion ◽  
Cardiac Metabolism ◽  
Pyruvate Dehydrogenase Kinase ◽  
Peroxisome Proliferator ◽  
Akt Phosphorylation ◽  
Isolated Hearts ◽  
Protein Levels

Genes encoding enzymes involved in fatty acids (FA) and glucose oxidation are transcriptionally regulated by peroxisome proliferator-activated receptors (PPAR), members of the nuclear receptor superfamily. Under conditions associated with O2 deficiency, PPAR-α modulates substrate switch (between FA and glucose) aimed at the adequate energy production to maintain basic cardiac function. Both, positive and negative effects of PPAR-α activation on myocardial ischemia/reperfusion (I/R) injury have been reported. Moreover, the role of PPAR-mediated metabolic shifts in cardioprotective mechanisms of preconditioning (PC) is relatively less investigated. We explored the effects of PPAR-α upregulation mimicking a delayed “second window” of PC on I/R injury in the rat heart and potential downstream mechanisms involved. Pretreatment of rats with PPAR-α agonist WY-14643 (WY, 1 mg/kg, i.p.) 24 h prior to I/R reduced post-ischemic stunning, arrhythmias and the extent of lethal injury (infarct size) and apoptosis (caspase-3 expression) in isolated hearts exposed to 30-min global ischemia and 2-h reperfusion. Protection was associated with remarkably increased expression of PPAR-α target genes promoting FA utilization (medium-chain acyl-CoA dehydrogenase, pyruvate dehydrogenase kinase-4 and carnitine palmitoyltransferase I) and reduced expression of glucose transporter GLUT-4 responsible for glucose transport and metabolism. In addition, enhanced Akt phosphorylation and protein levels of eNOS, in conjunction with blunting of cardioprotection by NOS inhibitor L-NAME, were observed in the WY-treated hearts. Conclusions: upregulation of PPAR-α target metabolic genes involved in FA oxidation may underlie a delayed phase PC-like protection in the rat heart. Potential non-genomic effects of PPAR-α–mediated cardioprotection may involve activation of prosurvival PI3K/Akt pathway and its downstream targets such as eNOS and subsequently reduced apoptosis.

scholarly journals Adipogenesis is differentially impaired by thyroid hormone receptor mutant isoforms

2010 ◽  
Vol 44 (4) ◽  
pp. 247-255 ◽  
Author(s):  
Alok Mishra ◽  
Xu-guang Zhu ◽  
Kai Ge ◽  
Sheue-Yann Cheng
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Fold Increase ◽  
Dominant Negative ◽  
Peroxisome Proliferator ◽  
Loss Of Function ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels

To understand the roles of thyroid hormone receptors (TRs) in adipogenesis, we adopted a loss-of-function approach. We generated 3T3-L1 cells stably expressing either TRα1 mutant (TRα1PV) or TRβ1 mutant (TRβ1PV). TRα1PV and TRβ1PV are dominant negative mutations with a frameshift in the C-terminal amino acids. In control cells, the thyroid hormone, tri-iodothyronine (T3), induced a 2.5-fold increase in adipogenesis in 3T3-L1 cells, as demonstrated by increased lipid droplets. This increase was mediated by T3-induced expression of the peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), which are master regulators of adipogenesis at both the mRNA and protein levels. In 3T3-L1 cells stably expressing TRα1PV (L1-α1PV cells) or TRβ1PV (L1-β1PV cells), adipogenesis was reduced 94 or 54% respectively, indicative of differential inhibitory activity of mutant TR isoforms. Concordantly, the expression of PPARγ and C/EBPα at the mRNA and protein levels was more repressed in L1-α1PV cells than in L1-β1PV cells. In addition, the expression of PPARγ downstream target genes involved in fatty acid synthesis – the lipoprotein lipase (Lpl) and aP2 involved in adipogenesis – was more inhibited by TRα1PV than by TRβ1PV. Chromatin immunoprecipitation assays showed that TRα1PV was more avidly recruited than TRβ1PV to the promoter to preferentially block the expression of the C/ebpα gene. Taken together, these data indicate that impaired adipogenesis by mutant TR is isoform dependent. The finding that induction of adipogenesis is differentially regulated by TR isoforms suggests that TR isoform-specific ligands could be designed for therapeutic intervention for lipid abnormalities.

Aging-induced decrease in the PPAR-α level in hearts is improved by exercise training

2002 ◽  
Vol 283 (5) ◽  
pp. H1750-H1760 ◽  
Author(s):  
Motoyuki Iemitsu ◽  
Takashi Miyauchi ◽  
Seiji Maeda ◽  
Takumi Tanabe ◽  
Masakatsu Takanashi ◽  
...  
Keyword(s):  
Enzyme Activity ◽  
Exercise Training ◽  
Target Genes ◽  
Molecular System ◽  
Metabolic Enzyme ◽  
Peroxisome Proliferator ◽  
Aged Rats ◽  
Peroxisome Proliferator Activated Receptor ◽  
Aged Rat ◽  
Protein Levels

Peroxisome proliferator-activated receptor (PPAR)-α, a transcriptional activator, regulates genes of fatty acid (FA) metabolic enzymes. To study the contribution of PPAR-α to exercise training-induced improvement of FA metabolic capacity in the aged heart, we investigated whether PPAR-α signaling and expression of its target genes in the aged heart are affected by exercise training. We used hearts of sedentary young rat (4 mo old), sedentary aged rat (23 mo old), and swim-trained aged rat (23 mo old, training for 8 wk). The mRNA and protein expression of PPAR-α in the heart was significantly lower in the sedentary aged rats compared with the sedentary young rats and was significantly higher in the swim-trained aged rats compared with the sedentary aged rats. The activity of PPAR-α DNA binding to the transcriptional regulating region on the FA metabolic enzyme genes, the mRNA expression of 3-hydroxyacyl CoA dehydrogenase (HAD) and carnitine palmitoyl transferase-I, which are PPAR-α target genes, and the enzyme activity of HAD in the heart altered in association with changes of the myocardial PPAR-α mRNA and protein levels. These findings suggest that exercise training improves aging-induced downregulation in myocardial PPAR-α-mediated molecular system, thereby contributing to the improvement of the FA metabolic enzyme activity in the trained-aged hearts.

Monocarboxylate transporters 1 and 4: expression and regulation by PPARα in ovine ruminal epithelial cells

2014 ◽  
Vol 307 (12) ◽  
pp. R1428-R1437 ◽  
Author(s):  
Franziska Benesch ◽  
Franziska Dengler ◽  
Franziska Masur ◽  
Helga Pfannkuche ◽  
Gotthold Gäbel
Keyword(s):  
Epithelial Cells ◽  
Intracellular Ph ◽  
Target Genes ◽  
Specific Inhibitor ◽  
Short Chain Fatty Acids ◽  
Monocarboxylate Transporter ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Selective Ligand

In the intact rumen epithelium, isoforms 1 and 4 of the monocarboxylate transporter (MCT1 and MCT4) are thought to play key roles in mediating transcellular and intracellular permeation of short-chain fatty acids and their metabolites and in maintaining intracellular pH. We examined whether both MCT1 and MCT4 are expressed at mRNA and protein levels in ovine ruminal epithelial cells (REC) maintained in primary culture and whether they are regulated by peroxisome proliferator-activated receptor-α (PPARα). Because both transporters have been characterized to function coupled to protons, the influence of PPARα on the recovery of intracellular pH after l-lactate exposure was evaluated by spectrofluorometry. MCT1 and MCT4 were detected using immunocytochemistry both at the cell margins and intracellularly in cultured REC. To test regulation by PPARα, cells were exposed to WY 14.643, a selective ligand of PPARα, for 48 h. The subsequent qPCR analysis resulted in a dose-dependent upregulation of MCT1 and PPARα target genes, whereas response of MCT4 was not uniform. Protein expression of MCT1 and MCT4 quantified by Western blot analysis was not altered by WY 14.643 treatment. l-Lactate-dependent proton export was blocked almost completely by pHMB, a specific inhibitor of MCT1 and MCT4. However, l-lactate-dependent, pHMB-inhibited proton export in WY 14.643-treated cells was not significantly altered compared with cells not treated with WY 14.643. These data suggest that PPARα is particularly regulating MCT1 but not MCT4 expression. Extent of lactate-coupled proton export indicates that MCT1 is already working on a high level even under unstimulated conditions.

scholarly journals Potential Candidate Genes for Alveolar Hypoxia Identified by Transcriptome Network Analysis

Medicina ◽  
2012 ◽  
Vol 48 (11) ◽  
pp. 84 ◽  
Author(s):  
Bi-li Zhang ◽  
Rong-liang Xu ◽  
Yong-wen Qin ◽  
Xing Zheng ◽  
Hong Wu ◽  
...  
Keyword(s):  
Network Analysis ◽  
Candidate Genes ◽  
Target Genes ◽  
Glucose Transporter ◽  
Kegg Pathway ◽  
Biological Response ◽  
Peroxisome Proliferator ◽  
Potential Candidate ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alveolar Hypoxia

Background. Alveolar hypoxia is an important condition related to many disorders such as chronic pulmonary hypertension, pulmonary vasoconstriction, and pulmonary vascular remodeling. The aim of present study was to disclose the biological response and the potential transcriptome networks regulating the hypoxia response in the lungs. Materials and Methods. In this study, the microarray dataset GSE11341 was used to construct a regulatory network and identify the potential genes related to alveolar hypoxia. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) term enrichment analyses were also performed. Results. Hypoxia inducible factor 1 alpha (HIF-1α), peroxisome proliferator-activated receptor gamma (PPARγ), and nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-кB) were to be the hub nodes in the transcriptome network. HIF-1α may regulate potassium voltagegated channel, shaker-related subfamily, member (5KCNA5), solute carrier family 2 (facilitated glucose transporter), member (1SLC2A1), and heme oxygenase (decycling) 1 (HMOX1) expression through the regulation of membrane potential, glucose metabolism, and anti-inflammation pathways. HMOX-1 mediates signaling pathways that relate to NF-кB. CCND1 (cyclin D1) expression could be regulated by PPARγ and HIF-1α via the cell cycle pathway. In addition, new transcriptional factors and target genes, such as phosphofructokinase (PFKL, liver), aldolase A (ALDOA, fructose-bisphosphate), and trefoil factor 3 (intestinal) (TFF3), were also identified. Conclusions. Transcriptome network analysis is a helpful method for the identification of the candidate genes in alveolar hypoxia. The KEGG pathway and GO term analysis are beneficial in the prediction of the underlying molecular mechanism of these identified genes in alveolar hypoxia.

scholarly journals Testosterone Replacement Modulates Cardiac Metabolic Remodeling after Myocardial Infarction by Upregulating PPARα

PPAR Research ◽  
2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Jing Yang ◽  
Fengyue Wang ◽  
Weiju Sun ◽  
Yanli Dong ◽  
Mingyu Li ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Fatty Acid ◽  
Cardiac Function ◽  
Glucose Transporter ◽  
Ischemic Heart ◽  
Testosterone Replacement ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Expression Of Genes ◽  
Metabolic Remodeling

Despite the importance of testosterone as a metabolic hormone, its effects on myocardial metabolism in the ischemic heart remain unclear. Myocardial ischemia leads to metabolic remodeling, ultimately resulting in ATP deficiency and cardiac dysfunction. In the present study, the effects of testosterone replacement on the ischemic heart were assessed in a castrated rat myocardial infarction model established by ligating the left anterior descending coronary artery 2 weeks after castration. The results of real-time PCR and Western blot analyses showed that peroxisome proliferator-activated receptorα(PPARα) decreased in the ischemic myocardium of castrated rats, compared with the sham-castration group, and the mRNA expression of genes involved in fatty acid metabolism (the fatty acid translocase CD36, carnitine palmitoyltransferase I, and medium-chain acyl-CoA dehydrogenase) and glucose transporter-4 also decreased. A decline in ATP levels in the castrated rats was accompanied by increased cardiomyocyte apoptosis and fibrosis and impaired cardiac function, compared with the sham-castration group, and these detrimental effects were reversed by testosterone replacement. Taken together, our findings suggest that testosterone can modulate myocardial metabolic remodeling by upregulating PPARαafter myocardial infarction, exerting a protective effect on cardiac function.

CREBL2, interacting with CREB, induces adipogenesis in 3T3-L1 adipocytes

2011 ◽  
Vol 439 (1) ◽  
pp. 27-38 ◽  
Author(s):  
Xi Ma ◽  
Heyu Zhang ◽  
Lan Yuan ◽  
Hao Jing ◽  
Phil Thacker ◽  
...  
Keyword(s):  
Glucose Transporter ◽  
Binding Protein ◽  
Critical Role ◽  
Camp Response Element Binding ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Glucose Transporter 1 ◽  
Creb Phosphorylation ◽  
Protein Levels ◽  
Element Binding Protein

The factors that influence preadipocyte determination remain poorly understood. In the present paper, we report that CREBL2 [CREB (cAMP-response-element-binding protein)-like 2], a novel bZIP_1 protein, is up-regulated during MDI-induced preadipocyte differentiation. During both overexpression and under physiological conditions, CREBL2 interacted and was entirely co-localized with CREB. Overexpression of CREBL2 was sufficient to promote adipogenesis via up-regulating the expression of PPARγ (peroxisome-proliferator-activated receptor γ) and C/EBPα (CCAAT/enhancer-binding protein α) and accelerate lipogenesis accompanied with increased GLUT (glucose transporter) 1 and GLUT4. CREBL2 knockdown restrained adipogenic conversion and lipogenesis. Additionally, depletion of CREB could completely block the effects of overexpressed CREBL2, whereas an increase in CREB could not drive adipogenesis in the absence of CREBL2, indicating that the roles for CREBL2 on adipogenesis were CREB-dependent. Furthermore, siCREBL2 [siRNA (short interfering RNA) against CREBL2] could down-regulate CREB transcriptional activity and suppress CREB phosphorylation. CREB knockdown decreased the CREBL2 protein levels and vice versa. Collectively, the results of the present study indicate that CREBL2 plays a critical role in adipogenesis and lipogenesis via interaction with CREB.

Etomoxir-induced PPARα-modulated enzymes protect during acute renal failure

2000 ◽  
Vol 278 (4) ◽  
pp. F667-F675 ◽  
Author(s):  
Didier Portilla ◽  
Gonghe Dai ◽  
Jeffrey M. Peters ◽  
Frank J. Gonzalez ◽  
Mark D. Crew ◽  
...  
Keyword(s):  
Target Genes ◽  
Ischemia Reperfusion ◽  
Kidney Tissue ◽  
Enzymatic Activities ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Protein Levels ◽  
Tubular Necrosis ◽  
Lower Blood ◽  
Significant Amelioration

Regulation of fatty acid β-oxidation (FAO) represents an important mechanism for a sustained balance of energy production/utilization in kidney tissue. To examine the role of stimulated FAO during ischemia, Etomoxir (Eto), clofibrate, and WY-14,643 compounds were given 5 days prior to the induction of ischemia/reperfusion (I/R) injury. Compared with rats administered vehicle, Eto-, clofibrate-, and WY-treated rats had lower blood urea nitrogen and serum creatinines following I/R injury. Histological analysis confirmed a significant amelioration of acute tubular necrosis. I/R injury led to a threefold reduction of mRNA and protein levels of acyl CoA oxidase (AOX) and cytochrome P4A1, as well as twofold inhibition of their enzymatic activities. Eto treatment prevented the reduction of mRNA and protein levels and the inhibition of the enzymatic activities of these two peroxisome proliferator-activated receptor-α (PPARα) target genes during I/R injury. PPARα null mice subjected to I/R injury demonstrated significantly enhanced cortical necrosis and worse kidney function compared with wild-type controls. These results suggest that upregulation of PPARα-modulated FAO genes has an important role in the observed cytoprotection during I/R injury.

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