scholarly journals PPARαin Obesity: Sex Difference and Estrogen Involvement

PPAR Research ◽  
2010 ◽  
Vol 2010 ◽  
pp. 1-16 ◽  
Author(s):  
Michung Yoon
Keyword(s):  
Target Genes ◽  
Molecular Level ◽  
Body Weight Gain ◽  
Lipoprotein Metabolism ◽  
Lipid Lowering ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ovariectomized Mice ◽  
Hepatic Fatty Acid Oxidation

Peroxisome proliferator-activated receptorα(PPARα) is a member of the steroid hormone receptor superfamily and is well known to act as the molecular target for lipid-lowering drugs of the fibrate family. At the molecular level, PPARαregulates the transcription of a number of genes critical for lipid and lipoprotein metabolism. PPARαactivators are further shown to reduce body weight gain and adiposity, at least in part, due to the increase of hepatic fatty acid oxidation and the decrease in levels of circulating triglycerides responsible for adipose cell hypertrophy and hyperplasia. However, these effects of the PPARαligand fenofibrate on obesity are regulated with sexual dimorphism and seem to be influenced by the presence of functioning ovaries, suggesting the involvement of ovarian steroids in the control of obesity by PPARα. In female ovariectomized mice, 17β-estradiol inhibits the actions of fenofibrate on obesity through its suppressive effects on the expression of PPARαtarget genes, and these processes may be mediated by inhibiting the coactivator recruitment of PPARα. Thus, it is likely that PPARαfunctions on obesity may be enhanced in estrogen-deficient states.

scholarly journals SIRT3 deficiency exacerbates fatty liver by attenuating the HIF1α-LIPIN 1 pathway and increasing CD36 through Nrf2

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Emma Barroso ◽  
Rosalía Rodríguez-Rodríguez ◽  
Mohammad Zarei ◽  
Javier Pizarro-Degado ◽  
Anna Planavila ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Redox Status ◽  
Acid Oxidation ◽  
Standard Diet ◽  
Peroxisome Proliferator ◽  
Lipid Uptake ◽  
Peroxisome Proliferator Activated Receptor ◽  
Vldl Receptor

Abstract Background Deficiency of mitochondrial sirtuin 3 (SIRT3), a NAD+-dependent protein deacetylase that maintains redox status and lipid homeostasis, contributes to hepatic steatosis. In this study, we investigated additional mechanisms that might play a role in aggravating hepatic steatosis in Sirt3-deficient mice fed a high-fat diet (HFD). Methods Studies were conducted in wild-type (WT) and Sirt3−/− mice fed a standard diet or a HFD and in SIRT3-knockdown human Huh-7 hepatoma cells. Results Sirt3−/− mice fed a HFD presented exacerbated hepatic steatosis that was accompanied by decreased expression and DNA-binding activity of peroxisome proliferator-activated receptor (PPAR) α and of several of its target genes involved in fatty acid oxidation, compared to WT mice fed the HFD. Interestingly, Sirt3 deficiency in liver and its knockdown in Huh-7 cells resulted in upregulation of the nuclear levels of LIPIN1, a PPARα co-activator, and of the protein that controls its levels and localization, hypoxia-inducible factor 1α (HIF-1α). These changes were prevented by lipid exposure through a mechanism that might involve a decrease in succinate levels. Finally, Sirt3−/− mice fed the HFD showed increased levels of some proteins involved in lipid uptake, such as CD36 and the VLDL receptor. The upregulation in CD36 was confirmed in Huh-7 cells treated with a SIRT3 inhibitor or transfected with SIRT3 siRNA and incubated with palmitate, an effect that was prevented by the Nrf2 inhibitor ML385. Conclusion These findings demonstrate new mechanisms by which Sirt3 deficiency contributes to hepatic steatosis. Graphical abstract

scholarly journals Estrogen-Related Receptor α Directs Peroxisome Proliferator-Activated Receptor α Signaling in the Transcriptional Control of Energy Metabolism in Cardiac and Skeletal Muscle

2004 ◽  
Vol 24 (20) ◽  
pp. 9079-9091 ◽  
Author(s):  
Janice M. Huss ◽  
Inés Pineda Torra ◽  
Bart Staels ◽  
Vincent Giguère ◽  
Daniel P. Kelly
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Target Genes ◽  
Cellular Fatty Acid ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Oxidation Rates

ABSTRACT Estrogen-related receptors (ERRs) are orphan nuclear receptors activated by the transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), a critical regulator of cellular energy metabolism. However, metabolic target genes downstream of ERRα have not been well defined. To identify ERRα-regulated pathways in tissues with high energy demand such as the heart, gene expression profiling was performed with primary neonatal cardiac myocytes overexpressing ERRα. ERRα upregulated a subset of PGC-1α target genes involved in multiple energy production pathways, including cellular fatty acid transport, mitochondrial and peroxisomal fatty acid oxidation, and mitochondrial respiration. These results were validated by independent analyses in cardiac myocytes, C2C12 myotubes, and cardiac and skeletal muscle of ERRα−/− mice. Consistent with the gene expression results, ERRα increased myocyte lipid accumulation and fatty acid oxidation rates. Many of the genes regulated by ERRα are known targets for the nuclear receptor PPARα, and therefore, the interaction between these regulatory pathways was explored. ERRα activated PPARα gene expression via direct binding of ERRα to the PPARα gene promoter. Furthermore, in fibroblasts null for PPARα and ERRα, the ability of ERRα to activate several PPARα targets and to increase cellular fatty acid oxidation rates was abolished. PGC-1α was also shown to activate ERRα gene expression. We conclude that ERRα serves as a critical nodal point in the regulatory circuitry downstream of PGC-1α to direct the transcription of genes involved in mitochondrial energy-producing pathways in cardiac and skeletal muscle.

scholarly journals Characterization of the transactivation domain in the peroxisome-proliferator-activated receptor γ co-activator (PGC-1)

2007 ◽  
Vol 403 (3) ◽  
pp. 511-518 ◽  
Author(s):  
Prabodh Sadana ◽  
Edwards A. Park
Keyword(s):  
Transcriptional Activation ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Transactivation Domain ◽  
Peroxisome Proliferator Activated Receptor ◽  
N Terminus ◽  
Cpt I

The PGC-1s (peroxisome-proliferator-activated receptor γ co-activators) are a family of transcriptional regulators that induce the expression of various metabolic genes. PGC-1 proteins stimulate genes involved in mitochondrial biogenesis, fatty acid oxidation and hepatic gluconeogenesis. Previous studies have demonstrated that the PGC-1α and β isoforms interact with nuclear receptors through the conserved LXXLL (leucine-X-X-leucine-leucine) motifs. In the present study, we have investigated the mechanisms by which these PGC-1 isoforms stimulate gene expression. We have determined that the N-terminus of PGC-1 is responsible for transcriptional activation. Two conserved peptide motifs were identified in the N-terminus of PGC-1α and β isoforms. These domains were named AD1 and AD2 (activation domain 1 and 2). Deletion of both of these motifs decreased the induction of various PGC-1-regulated genes including the PEPCK (phosphoenolpyruvate carboxykinase) and CPT-I (carnitine palmitoyltransferase-I) genes. It was determined that amino acids containing a negative charge in AD1 and the leucine residues in AD2 were important for the transcriptional induction of the PEPCK and CPT-I genes. Disruption of the AD motifs did not diminish the ability of the PGC-1α protein to associate with the PEPCK or CPT-I genes. In addition, deletion of the AD domains did not eliminate the ability of PGC-1α to interact with the thyroid hormone receptor. The data indicate that the AD1 and AD2 motifs mediate the induction of many PGC-1- responsive genes, but they do not contribute to the recruitment of PGC-1 to target genes.

scholarly journals The Peroxisome Proliferator-Activated Receptor N-Terminal Domain Controls Isotype-Selective Gene Expression and Adipogenesis

2006 ◽  
Vol 20 (6) ◽  
pp. 1261-1275 ◽  
Author(s):  
Sarah Hummasti ◽  
Peter Tontonoz
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Target Genes ◽  
Biological Effects ◽  
Binding Domain ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
N Terminus

Abstract Peroxisome proliferator-activated receptors (PPARγ, PPARα, and PPARδ) are important regulators of lipid metabolism. Although they share significant structural similarity, the biological effects associated with each PPAR isotype are distinct. For example, PPARα and PPARδ regulate fatty acid catabolism, whereas PPARγ controls lipid storage and adipogenesis. The different functions of PPARs in vivo can be explained at least in part by the different tissue distributions of the three receptors. The question of whether the receptors have different intrinsic activities and regulate distinct target genes, however, has not been adequately explored. We have engineered cell lines that express comparable amounts of each receptor. Transcriptional profiling of these cells in the presence of selective agonists reveals partially overlapping but distinct patterns of gene regulation by the three PPARs. Moreover, analysis of chimeric receptors points to the N terminus of each receptor as the key determinant of isotype-selective gene expression. For example, the N terminus of PPARγ confers the ability to promote adipocyte differentiation when fused to the PPARδ DNA binding domain and ligand binding domain, whereas the N terminus of PPARδ leads to the inappropriate expression of fatty acid oxidation genes in differentiated adipocytes when fused to PPARγ. Finally, we demonstrate that the N terminus of each receptor functions in part to limit receptor activity because deletion of the N terminus leads to nonselective activation of target genes. A more detailed understanding of the mechanisms by which the individual PPARs differentially regulate gene expression should aid in the design of more effective drugs, including tissue- and target gene-selective PPAR modulators.

scholarly journals Citrus ichangensisPeel Extract Exhibits Anti-Metabolic Disorder Effects by the Inhibition of PPARγand LXR Signaling in High-Fat Diet-Induced C57BL/6 Mouse

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Xiaobo Ding ◽  
Shengjie Fan ◽  
Yan Lu ◽  
Yu Zhang ◽  
Ming Gu ◽  
...  
Keyword(s):  
Fatty Acid Synthase ◽  
Target Genes ◽  
Body Weight Gain ◽  
Density Lipoprotein ◽  
Chow Diet ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Nutritional Disorder ◽  
Peroxisome Proliferator Activated Receptor ◽  
Diet Induced Obesity

Obesity is a common nutritional disorder associated with type 2 diabetes, cardiovascular diseases, dyslipidemia, and certain cancers. In this study, we investigated the effects ofCitrus ichangensispeel extract (CIE) in high-fat (HF) diet-induced obesity mice. Female C57BL/6 mice were fed a chow diet or an HF diet alone or supplemented with 1% w/w CIE for 8 weeks. We found that CIE treatment could lower blood glucose level and improve glucose tolerance. In the HF+CIE group, body weight gain, serum total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-c) levels, and liver triglyceride (TG) and TC concentrations were significantly (P<0.05) decreased relative to those in the HF group. To elucidate the mechanism of CIE on the metabolism of glucose and lipid, related genes expression in liver were examined. In liver tissue, CIE significantly decreased the mRNA expression levels of peroxisome proliferator-activated receptorγ(PPARγ) and its target genes, such as fatty acid synthase (FAS) and acyl-CoA oxidase (ACO). Moreover, CIE also decreased the expression of liver X receptor (LXR)αandβwhich are involved in lipid and glucose metabolism. These results suggest that CIE administration could alleviate obesity and related metabolic disorders in HF diet-induced obesity mice through the inhibition of PPARγand LXR signaling.

scholarly journals Hepatic Cerebroside Sulfotransferase Is Induced by PPARα Activation in Mice

PPAR Research ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Takefumi Kimura ◽  
Takero Nakajima ◽  
Yuji Kamijo ◽  
Naoki Tanaka ◽  
Lixuan Wang ◽  
...  
Keyword(s):  
Target Genes ◽  
Control Diet ◽  
Lipoprotein Metabolism ◽  
Protective Role ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolism Enzymes ◽  
Key Enzyme

Sulfatides are one of the major sphingoglycolipids in mammalian serum and are synthesized and secreted mainly from the liver as a component of lipoproteins. Recent studies revealed a protective role for serum sulfatides against arteriosclerosis and hypercoagulation. Although peroxisome proliferator-activated receptor (PPAR)αhas important functions in hepatic lipoprotein metabolism, its association with sulfatides has not been investigated. In this study, sulfatide levels and the expression of enzymes related to sulfatide metabolism were examined using wild-type (+/+),Ppara-heterozygous (+/−), andPpara-null (−/−) mice given a control diet or one containing 0.1% fenofibrate, a clinically used hypolipidemic drug and PPARαactivator. Fenofibrate treatment increased serum and hepatic sulfatides inPpara(+/+) and (+/−) mice through a marked induction of hepatic cerebroside sulfotransferase (CST), a key enzyme in sulfatide synthesis, in a PPARα-dependent manner. Furthermore, increases in CST mRNA levels were correlated with mRNA elevations of several known PPARαtarget genes, and such changes were not observed for other sulfatide-metabolism enzymes in the liver. These results suggest that PPARαactivation enhances hepatic sulfatide synthesis via CST induction and implicate CST as a novel PPARαtarget gene.

PPAR-α effects on the heart and other vascular tissues

2003 ◽  
Vol 285 (1) ◽  
pp. H1-H9 ◽  
Author(s):  
Gordon A. Francis ◽  
Jean-Sébastien Annicotte ◽  
Johan Auwerx
Keyword(s):  
Vessel Wall ◽  
Arterial Wall ◽  
Current Knowledge ◽  
Lipoprotein Metabolism ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Main Role ◽  
Peroxisome Proliferator Activated Receptor ◽  
Hypolipidemic Agents ◽  
Deficient Mice

Peroxisome proliferator-activated receptor (PPAR)-α is a member of a large nuclear receptor superfamily whose main role is to activate genes involved in fatty acid oxidation in the liver, heart, kidney, and skeletal muscle. While currently used mainly as hypolipidemic agents, the cardiac effects and anti-inflammatory actions of PPAR-α agonists in arterial wall cells suggest other potential cardioprotective and antiatherosclerotic effects of these agents. This review summarizes current knowledge regarding the effects of PPAR-α agonists on lipid and lipoprotein metabolism, the heart, and the vessel wall and introduces some of the insights gained in these areas from studying PPAR-α-deficient mice. The introduction of new and more potent PPAR-α agonists will provide important insights into the overall benefits of activating PPAR-α clinically for the treatment of dyslipidemia and prevention of vascular disease.

scholarly journals SIRT4 Represses Peroxisome Proliferator-Activated Receptor α Activity To Suppress Hepatic Fat Oxidation

2013 ◽  
Vol 33 (22) ◽  
pp. 4552-4561 ◽  
Author(s):  
Gaëlle Laurent ◽  
Vincent C. J. de Boer ◽  
Lydia W. S. Finley ◽  
Meredith Sweeney ◽  
Hong Lu ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Oxidation ◽  
Target Genes ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Oxidation Rates ◽  
Hepatic Fat ◽  
Important Regulator

Sirtuins are a family of protein deacetylases, deacylases, and ADP-ribosyltransferases that regulate life span, control the onset of numerous age-associated diseases, and mediate metabolic homeostasis. We have uncovered a novel role for the mitochondrial sirtuin SIRT4 in the regulation of hepatic lipid metabolism during changes in nutrient availability. We show that SIRT4 levels decrease in the liver during fasting and that SIRT4 null mice display increased expression of hepatic peroxisome proliferator-activated receptor α (PPARα) target genes associated with fatty acid catabolism. Accordingly, primary hepatocytes from SIRT4 knockout (KO) mice exhibit higher rates of fatty acid oxidation than wild-type hepatocytes, and SIRT4 overexpression decreases fatty acid oxidation rates. The enhanced fatty acid oxidation observed in SIRT4 KO hepatocytes requires functional SIRT1, demonstrating a clear cross talk between mitochondrial and nuclear sirtuins. Thus, SIRT4 is a new component of mitochondrial signaling in the liver and functions as an important regulator of lipid metabolism.

scholarly journals Role of peroxisome proliferator-activated receptor alpha in the expression of hepatic fatty acid oxidation-related genes in chickens

2015 ◽  
Vol 87 (1) ◽  
pp. 61-66 ◽  
Author(s):  
Kazuhisa Honda ◽  
Takaoki Saneyasu ◽  
Haruka Sugimoto ◽  
Kiyotaka Kurachi ◽  
Shoko Takagi ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Receptor Alpha ◽  
Hepatic Fatty Acid ◽  
Hepatic Fatty Acid Oxidation

scholarly journals Peroxisome proliferator-activated receptor β/δ: a master regulator of metabolic pathways in skeletal muscle

2010 ◽  
Vol 4 (2) ◽  
Author(s):  
Shawon Lahiri ◽  
Walter Wahli
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Energy Expenditure ◽  
Skeletal Muscles ◽  
Metabolic Disorders ◽  
Therapeutic Interventions ◽  
Lipid Lowering ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

AbstractSkeletal muscle is considered to be a major site of energy expenditure and thus is important in regulating events affecting metabolic disorders. Over the years, both in vitro and in vivo approaches have established the role of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in fatty acid metabolism and energy expenditure in skeletal muscles. Pharmacological activation of PPARβ/δ by specific ligands regulates the expression of genes involved in lipid use, triglyceride hydrolysis, fatty acid oxidation, energy expenditure, and lipid efflux in muscles, in turn resulting in decreased body fat mass and enhanced insulin sensitivity. Both the lipid-lowering and the anti-diabetic effects exerted by the induction of PPARβ/δ result in the amelioration of symptoms of metabolic disorders. This review summarizes the action of PPARβ/δ activation in energy metabolism in skeletal muscles and also highlights the unexplored pathways in which it might have potential effects in the context of muscular disorders. Numerous preclinical studies have identified PPARβ/δ as a probable potential target for therapeutic interventions. Although PPARβ/δ agonists have not yet reached the market, several are presently being investigated in clinical trials.

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