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Search Results: 1 - 10 of 1044 matches for " Sander Kersten "
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Peroxisome Proliferator Activated Receptors and Lipoprotein Metabolism
Sander Kersten
PPAR Research , 2008, DOI: 10.1155/2008/132960
Abstract: Plasma lipoproteins are responsible for carrying triglycerides and cholesterol in the blood and ensuring their delivery to target organs. Regulation of lipoprotein metabolism takes place at numerous levels including via changes in gene transcription. An important group of transcription factors that mediates the effect of dietary fatty acids and certain drugs on plasma lipoproteins are the peroxisome proliferator activated receptors (PPARs). Three PPAR isotypes can be distinguished, all of which have a major role in regulating lipoprotein metabolism. PPAR is the molecular target for the fibrate class of drugs. Activation of PPAR in mice and humans markedly reduces hepatic triglyceride production and promotes plasma triglyceride clearance, leading to a clinically significant reduction in plasma triglyceride levels. In addition, plasma high-density lipoprotein (HDL)-cholesterol levels are increased upon PPAR activation in humans. PPAR is the molecular target for the thiazolidinedione class of drugs. Activation of PPAR in mice and human is generally associated with a modest increase in plasma HDL-cholesterol and a decrease in plasma triglycerides. The latter effect is caused by an increase in lipoprotein lipase-dependent plasma triglyceride clearance. Analogous to PPAR, activation of PPAR/ leads to increased plasma HDL-cholesterol and decreased plasma triglyceride levels. In this paper, a fresh perspective on the relation between PPARs and lipoprotein metabolism is presented. The emphasis is on the physiological role of PPARs and the mechanisms underlying the effect of synthetic PPAR agonists on plasma lipoprotein levels.
PPARS and Obesity
Francine M. Gregoire,Sander Kersten,Wallace Harrington
PPAR Research , 2007, DOI: 10.1155/2007/78475
Abstract:
Peroxisome Proliferator-Activated Receptor Alpha Target Genes
Maryam Rakhshandehroo,Bianca Knoch,Michael Müller,Sander Kersten
PPAR Research , 2010, DOI: 10.1155/2010/612089
Abstract: The peroxisome proliferator-activated receptor alpha (PPAR ) is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPAR serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPAR binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPAR governs biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPAR is directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPAR in lipid metabolism and other pathways through a detailed analysis of the different known or putative PPAR target genes. The emphasis is on gene regulation by PPAR in liver although many of the results likely apply to other organs and tissues as well. 1. Introduction Nutrient metabolism and energy homeostasis are tightly controlled by numerous regulatory systems involving specific transcription factors. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the superfamily of nuclear hormone receptors and play an important role in nutrient homeostasis [1–3]. Three different PPAR subtypes are known: and All PPARs share the same molecular mode of action via formation of heterodimers with the nuclear receptor RXR, followed by binding to specific DNA-response elements in target genes known as peroxisome proliferator response elements (PPREs). PPREs are characterized by a common core sequence consisting of a direct repeat of the consensus sequence AGGTCA interspaced by a single nucleotide [1, 4]. Expression of and is found ubiquitously, whereas is mainly expressed in adipose tissue, macrophages, and colon [5, 6]. Activation of transcription by PPARs is dependent on a number of different steps including ligand binding to PPAR, binding of PPAR to the target gene, removal of corepressors and recruitment of coactivators, remodeling of the chromatin structure, and finally facilitation of gene transcription [7]. This paper will focus exclusively on ? was first discovered in the early 1990s and since then has been identified as the master regulator of hepatic lipid metabolism [8]. In addition, has been shown to govern glucose metabolism, lipoprotein metabolism, liver inflammation, amino acid metabolism, and hepatocyte proliferation (specifically in rodents). Synthetic agonists of lower plasma triglycerides
PPARs, Obesity, and Inflammation
Rinke Stienstra,Caroline Duval,Michael Müller,Sander Kersten
PPAR Research , 2007, DOI: 10.1155/2007/95974
Abstract: The worldwide prevalence of obesity and related metabolic disorders is rising rapidly, increasing the burden on our healthcare system. Obesity is often accompanied by excess fat storage in tissues other than adipose tissue, including liver and skeletal muscle, which may lead to local insulin resistance and may stimulate inflammation, as in steatohepatitis. In addition, obesity changes the morphology and composition of adipose tissue, leading to changes in protein production and secretion. Some of these secreted proteins, including several proinflammatory mediators, may be produced by macrophages resident in the adipose tissue. The changes in inflammatory status of adipose tissue and liver with obesity feed a growing recognition that obesity represents a state of chronic low-level inflammation. Various molecular mechanisms have been implicated in obesity-induced inflammation, some of which are modulated by the peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated transcription factors involved in the regulation of numerous biological processes, including lipid and glucose metabolism, and overall energy homeostasis. Importantly, PPARs also modulate the inflammatory response, which makes them an interesting therapeutic target to mitigate obesity-induced inflammation and its consequences. This review will address the role of PPARs in obesity-induced inflammation specifically in adipose tissue, liver, and the vascular wall.
Comparative Analysis of Gene Regulation by the Transcription Factor PPARα between Mouse and Human
Maryam Rakhshandehroo, Guido Hooiveld, Michael Müller, Sander Kersten
PLOS ONE , 2009, DOI: 10.1371/journal.pone.0006796
Abstract: Background Studies in mice have shown that PPARα is an important regulator of hepatic lipid metabolism and the acute phase response. However, little information is available on the role of PPARα in human liver. Here we set out to compare the function of PPARα in mouse and human hepatocytes via analysis of target gene regulation. Methodology/Principal Findings Primary hepatocytes from 6 human and 6 mouse donors were treated with PPARα agonist Wy14643 and gene expression profiling was performed using Affymetrix GeneChips followed by a systems biology analysis. Baseline PPARα expression was similar in human and mouse hepatocytes. Depending on species and time of exposure, Wy14643 significantly induced the expression of 362–672 genes. Surprisingly minor overlap was observed between the Wy14643-regulated genes from mouse and human, although more substantial overlap was observed at the pathway level. Xenobiotics metabolism and apolipoprotein synthesis were specifically regulated by PPARα in human hepatocytes, whereas glycolysis-gluconeogenesis was regulated specifically in mouse hepatocytes. Most of the genes commonly regulated in mouse and human were involved in lipid metabolism and many represented known PPARα targets, including CPT1A, HMGCS2, FABP1, ACSL1, and ADFP. Several genes were identified that were specifically induced by PPARα in human (MBL2, ALAS1, CYP1A1, TSKU) or mouse (Fbp2, lgals4, Cd36, Ucp2, Pxmp4). Furthermore, several putative novel PPARα targets were identified that were commonly regulated in both species, including CREB3L3, KLF10, KLF11 and MAP3K8. Conclusions/Significance Our results suggest that PPARα activation has a major impact on gene regulation in human hepatocytes. Importantly, the role of PPARα as master regulator of hepatic lipid metabolism is generally well-conserved between mouse and human. Overall, however, PPARα regulates a mostly divergent set of genes in mouse and human hepatocytes.
Comprehensive Analysis of PPAR-Dependent Regulation of Hepatic Lipid Metabolism by Expression Profiling
Maryam Rakhshandehroo,Linda M. Sanderson,Merja Matilainen,Rinke Stienstra,Carsten Carlberg,Philip J. de Groot,Michael Müller,Sander Kersten
PPAR Research , 2007, DOI: 10.1155/2007/26839
Abstract: PPARα is a ligand-activated transcription factor involved in the regulation of nutrient metabolism and inflammation. Although much is already known about the function of PPARα in hepatic lipid metabolism, many PPARα-dependent pathways and genes have yet to be discovered. In order to obtain an overview of PPARα-regulated genes relevant to lipid metabolism, and to probe for novel candidate PPARα target genes, livers from several animal studies in which PPARα was activated and/or disabled were analyzed by Affymetrix GeneChips. Numerous novel PPARα-regulated genes relevant to lipid metabolism were identified. Out of this set of genes, eight genes were singled out for study of PPARα-dependent regulation in mouse liver and in mouse, rat, and human primary hepatocytes, including thioredoxin interacting protein (Txnip), electron-transferring-flavoprotein β polypeptide (Etfb), electron-transferring-flavoprotein dehydrogenase (Etfdh), phosphatidylcholine transfer protein (Pctp), endothelial lipase (EL, Lipg), adipose triglyceride lipase (Pnpla2), hormone-sensitive lipase (HSL, Lipe), and monoglyceride lipase (Mgll). Using an in silico screening approach, one or more PPAR response elements (PPREs) were identified in each of these genes. Regulation of Pnpla2, Lipe, and Mgll, which are involved in triglyceride hydrolysis, was studied under conditions of elevated hepatic lipids. In wild-type mice fed a high fat diet, the decrease in hepatic lipids following treatment with the PPARα agonist Wy14643 was paralleled by significant up-regulation of Pnpla2, Lipe, and Mgll, suggesting that induction of triglyceride hydrolysis may contribute to the anti-steatotic role of PPARα. Our study illustrates the power of transcriptional profiling to uncover novel PPARα-regulated genes and pathways in liver.
Linking nutritional regulation of Angptl4, Gpihbp1, and Lmf1 to lipoprotein lipase activity in rodent adipose tissue
Olessia Kroupa, Evelina Vorrsj?, Rinke Stienstra, Frits Mattijssen, Stefan K Nilsson, Valentina Sukonina, Sander Kersten, Gunilla Olivecrona, Thomas Olivecrona
BMC Physiology , 2012, DOI: 10.1186/1472-6793-12-13
Abstract: The system underwent moderate circadian oscillations, for LPL in phase with food intake, for ANGPTL4 and GPIHBP1 in the opposite direction. Studies with cycloheximide showed that whereas LPL protein turns over rapidly, ANGPTL4 protein turns over more slowly. Studies with the transcription blocker Actinomycin D showed that transcripts for ANGPTL4 and GPIHBP1, but not LMF1 or LPL, turn over rapidly. When food was withdrawn the expression of ANGPTL4 and GPIHBP1 increased rapidly, and LPL activity decreased. On re-feeding and after injection of insulin the expression of ANGPTL4 and GPIHBP1 decreased rapidly, and LPL activity increased. In ANGPTL4?/? mice adipose tissue LPL activity did not show these responses. In old, obese rats that showed signs of insulin resistance, the responses of ANGPTL4 and GPIHBP1 mRNA and of LPL activity were severely blunted (at 26?weeks of age) or almost abolished (at 52?weeks of age).This study demonstrates directly that ANGPTL4 is necessary for rapid modulation of LPL activity in adipose tissue. ANGPTL4 message levels responded very rapidly to changes in the nutritional state. LPL activity always changed in the opposite direction. This did not happen in Angptl4?/? mice. GPIHBP1 message levels also changed rapidly and in the same direction as ANGPTL4, i.e. increased on fasting when LPL activity decreased. This was unexpected because GPIHBP1 is known to stabilize LPL. The plasticity of the LPL system is severely blunted or completely lost in insulin resistant rats.Lipoprotein lipase (LPL) is produced by parenchymal cells in some tissues (e.g. adipocytes, myocytes), secreted, and transported to the luminal side of capillaries. Here the enzyme hydrolyzes triglycerides in chylomicrons and VLDL and thereby makes fatty acids available for tissue metabolism. LPL activity is rapidly modulated by the nutritional state and plays a major role in distribution of fatty acids between tissues [1,2] .The rapid daily modulations of LPL activity are mainly p
Pronounced Effects of Acute Endurance Exercise on Gene Expression in Resting and Exercising Human Skeletal Muscle
Milène Catoire, Marco Mensink, Mark V. Boekschoten, Roland Hangelbroek, Michael Müller, Patrick Schrauwen, Sander Kersten
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0051066
Abstract: Regular physical activity positively influences whole body energy metabolism and substrate handling in exercising muscle. While it is recognized that the effects of exercise extend beyond exercising muscle, it is unclear to what extent exercise impacts non-exercising muscles. Here we investigated the effects of an acute endurance exercise bouts on gene expression in exercising and non-exercising human muscle. To that end, 12 male subjects aged 44–56 performed one hour of one-legged cycling at 50% Wmax. Muscle biopsies were taken from the exercising and non-exercising leg before and immediately after exercise and analyzed by microarray. One-legged cycling raised plasma lactate, free fatty acids, cortisol, noradrenalin, and adrenalin levels. Surprisingly, acute endurance exercise not only caused pronounced gene expression changes in exercising muscle but also in non-exercising muscle. In the exercising leg the three most highly induced genes were all part of the NR4A family. Remarkably, many genes induced in non-exercising muscle were PPAR targets or related to PPAR signalling, including PDK4, ANGPTL4 and SLC22A5. Pathway analysis confirmed this finding. In conclusion, our data indicate that acute endurance exercise elicits pronounced changes in gene expression in non-exercising muscle, which are likely mediated by changes in circulating factors such as free fatty acids. The study points to a major influence of exercise beyond the contracting muscle.
Effect of Synthetic Dietary Triglycerides: A Novel Research Paradigm for Nutrigenomics
Linda M. Sanderson, Philip J. de Groot, Guido J. E. J. Hooiveld, Arjen Koppen, Eric Kalkhoven, Michael Müller, Sander Kersten
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0001681
Abstract: Background The effect of dietary fats on human health and disease are likely mediated by changes in gene expression. Several transcription factors have been shown to respond to fatty acids, including SREBP-1c, NF-κB, RXRs, LXRs, FXR, HNF4α, and PPARs. However, it is unclear to what extent these transcription factors play a role in gene regulation by dietary fatty acids in vivo. Methodology/Principal Findings Here, we take advantage of a unique experimental design using synthetic triglycerides composed of one single fatty acid in combination with gene expression profiling to examine the effects of various individual dietary fatty acids on hepatic gene expression in mice. We observed that the number of significantly changed genes and the fold-induction of genes increased with increasing fatty acid chain length and degree of unsaturation. Importantly, almost every single gene regulated by dietary unsaturated fatty acids remained unaltered in mice lacking PPARα. In addition, the majority of genes regulated by unsaturated fatty acids, especially docosahexaenoic acid, were also regulated by the specific PPARα agonist WY14643. Excellent agreement was found between the effects of unsaturated fatty acids on mouse liver versus cultured rat hepatoma cells. Interestingly, using Nuclear Receptor PamChip? Arrays, fatty acid- and WY14643-induced interactions between PPARα and coregulators were found to be highly similar, although several PPARα-coactivator interactions specific for WY14643 were identified. Conclusions/Significance We conclude that the effects of dietary unsaturated fatty acids on hepatic gene expression are almost entirely mediated by PPARα and mimic those of synthetic PPARα agonists in terms of regulation of target genes and molecular mechanism. Use of synthetic dietary triglycerides may provide a novel paradigm for nutrigenomics research.
Analysis of the heat shock response in mouse liver reveals transcriptional dependence on the nuclear receptor peroxisome proliferator-activated receptor α (PPARα)
Beena Vallanat, Steven P Anderson, Holly M Brown-Borg, Hongzu Ren, Sander Kersten, Sudhakar Jonnalagadda, Rajagopalan Srinivasan, J Christopher Corton
BMC Genomics , 2010, DOI: 10.1186/1471-2164-11-16
Abstract: Wild-type and PPARα-null mice were exposed to HS, the PPARα agonist WY-14,643 (WY), or both; gene and protein expression was examined in the livers of the mice 4 or 24 hrs after HS. Gene expression profiling identified a number of Hsp family members that were altered similarly in both mouse strains. However, most of the targets of HS did not overlap between strains. A subset of genes was shown by microarray and RT-PCR to be regulated by HS in a PPARα-dependent manner. HS also down-regulated a large set of mitochondrial genes specifically in PPARα-null mice that are known targets of PPARγ co-activator-1 (PGC-1) family members. Pretreatment of PPARα-null mice with WY increased expression of PGC-1β and target genes and prevented the down-regulation of the mitochondrial genes by HS. A comparison of HS genes regulated in our dataset with those identified in wild-type and HSF1-null mouse embryonic fibroblasts indicated that although many HS genes are regulated independently of both PPARα and HSF1, a number require both factors for HS responsiveness.These findings demonstrate that the PPARα genotype has a dramatic effect on the transcriptional targets of HS and support an expanded role for PPARα in the regulation of proteome maintenance genes after exposure to diverse forms of environmental stress including HS.Physiological and chemical stresses produce disease states in which proteins are damaged or misfolded in part through increases in oxidative stress. Many endogenous pathways are engaged in restoring cellular homeostasis, including stabilization of unfolded proteins to prevent aggregation and removing damaged or excess proteins through proteolysis. Stabilization of unfolded proteins is performed by molecular chaperones that assist in the folding of nascent polypeptides. Many genes encoding for chaperones exhibit increased expression after exposure to a wide variety of stimuli including chemical exposure or increased temperatures and are thus called heat shock (HS) pro
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