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1.  Peroxisome Proliferator-Activated Receptor Alpha Target Genes 
PPAR Research  2010;2010:612089.
The peroxisome proliferator-activated receptor alpha (PPARα) 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. PPARα serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPARα binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPARα governs biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPARα is directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPARα in lipid metabolism and other pathways through a detailed analysis of the different known or putative PPARα target genes. The emphasis is on gene regulation by PPARα in liver although many of the results likely apply to other organs and tissues as well.
doi:10.1155/2010/612089
PMCID: PMC2948931  PMID: 20936127
2.  PPARα Ligands as Antitumorigenic and Antiangiogenic Agents 
PPAR Research  2008;2008:906542.
Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor family of ligand-activated transcription factors. This subfamily is composed of three members—PPARα, PPARδ, and PPARγ—that differ in their cell and tissue distribution as well as in their target genes. PPARα is abundantly expressed in liver, brown adipose tissue, kidney, intestine, heart, and skeletal muscle; and its ligands have been used to treat diseases such as obesity and diabetes. The recent finding that members of the PPAR family, including the PPARα, are expressed by tumor and endothelial cells together with the observation that PPAR ligands regulate cell growth, survival, migration, and invasion, suggested that PPARs also play a role in cancer. In this review, we focus on the contribution of PPARα to tumor and endothelial cell functions and provide compelling evidence that PPARα can be viewed as a new class of ligand activated tumor “suppressor” gene with antiangiogenic and antitumorigenic activities. Given that PPAR ligands are currently used in medicine as hypolipidemic drugs with excellent tolerance and limited toxicity, PPARα activation might offer a novel and potentially low-toxic approach for the treatment of tumor-associated angiogenesis and cancer.
doi:10.1155/2008/906542
PMCID: PMC2517125  PMID: 18725983
3.  The cardiac phenotype induced by PPARα overexpression mimics that caused by diabetes mellitus 
Recent evidence has defined an important role for PPARα in the transcriptional control of cardiac energy metabolism. To investigate the role of PPARα in the genesis of the metabolic and functional derangements of diabetic cardiomyopathy, mice with cardiac-restricted overexpression of PPARα (MHC-PPAR) were produced and characterized. The expression of PPARα target genes involved in cardiac fatty acid uptake and oxidation pathways was increased in MHC-PPAR mice. Surprisingly, the expression of genes involved in glucose transport and utilization was reciprocally repressed in MHC-PPAR hearts. Consistent with the gene expression profile, myocardial fatty acid oxidation rates were increased and glucose uptake and oxidation decreased in MHC-PPAR mice, a metabolic phenotype strikingly similar to that of the diabetic heart. MHC-PPAR hearts exhibited signatures of diabetic cardiomyopathy including ventricular hypertrophy, activation of gene markers of pathologic hypertrophic growth, and transgene expression–dependent alteration in systolic ventricular dysfunction. These results demonstrate that (a) PPARα is a critical regulator of myocardial fatty acid uptake and utilization, (b) activation of cardiac PPARα regulatory pathways results in a reciprocal repression of glucose uptake and utilization pathways, and (c) derangements in myocardial energy metabolism typical of the diabetic heart can become maladaptive, leading to cardiomyopathy.
doi:10.1172/JCI14080
PMCID: PMC150824  PMID: 11781357
4.  Advances in understanding the regulation of apoptosis and mitosis by peroxisome-proliferator activated receptors in pre-clinical models: relevance for human health and disease 
Peroxisome proliferator activated receptors (PPARs) are a family of related receptors implicated in a diverse array of biological processes. There are 3 main isotypes of PPARs known as PPARα, PPARβ and PPARγ and each is organized into domains associated with a function such as ligand binding, activation and DNA binding. PPARs are activated by ligands, which can be both endogenous such as fatty acids or their derivatives, or synthetic, such as peroxisome proliferators, hypolipidaemic drugs, anti-inflammatory or insulin-sensitizing drugs. Once activated, PPARs bind to DNA and regulate gene transcription. The different isotypes differ in their expression patterns, lending clues on their function. PPARα is expressed mainly in liver whereas PPARγ is expressed in fat and in some macrophages. Activation of PPARα in rodent liver is associated with peroxisome proliferation and with suppression of apoptosis and induction of cell proliferation. The mechanism by which activation of PPARα regulates apoptosis and proliferation is unclear but is likely to involve target gene transcription. Similarly, PPARγ is involved in the induction of cell growth arrest occurring during the differentiation process of fibroblasts to adipocytes. However, it has been implicated in the regulation of cell cycle and cell proliferation in colon cancer models. Less in known concerning PPARβ but it was identified as a downstream target gene for APC/β-catenin/T cell factor-4 tumor suppressor pathway, which is involved in the regulation of growth promoting genes such as c-myc and cyclin D1. Marked species and tissue differences in the expression of PPARs complicate the extrapolation of pre-clinical data to humans. For example, PPARα ligands such as the hypolipidaemic fibrates have been used extensively in the clinic over the past 20 years to treat cardiovascular disease and side effects of clinical fibrate use are rare, despite the observation that these compounds are rodent carcinogens. Similarly, adverse clinical responses have been seen with PPARγ ligands that were not predicted by pre-clinical models. Here, we consider the response to PPAR ligands seen in pre-clinical models of efficacy and safety in the context of human health and disease.
doi:10.1186/1476-5926-2-3
PMCID: PMC151270  PMID: 12622871
5.  The PPARα-Humanized Mouse: A Model to Investigate Species Differences in Liver Toxicity Mediated by PPARα 
To determine the impact of the species difference between rodents and humans in response to peroxisome proliferators (PPs) mediated by peroxisome proliferator–activated receptor (PPAR)α, PPARα-humanized transgenic mice were generated using a P1 phage artificial chromosome (PAC) genomic clone bred onto a pparα-null mouse background, designated hPPARαPAC. In hPPARαPAC mice, the human PPARα gene is expressed in tissues with high fatty acid catabolism and induced upon fasting, similar to mouse PPARα in wild-type (Wt) mice. Upon treatment with the PP fenofibrate, hPPARαPAC mice exhibited responses similar to Wt mice, including peroxisome proliferation, lowering of serum triglycerides, and induction of PPARα target genes encoding enzymes involved in fatty acid metabolism in liver, kidney, and heart, suggesting that human PPARα (hPPARα) functions in the same manner as mouse PPARα in regulating fatty acid metabolism and lowering serum triglycerides. However, in contrast to Wt mice, treatment of hPPARαPAC mice with fenofibrate did not cause significant hepatomegaly and hepatocyte proliferation, thus indicating that the mechanisms by which PPARα affects lipid metabolism are distinct from the hepatocyte proliferation response, the latter of which is only induced by mouse PPARα. In addition, a differential regulation of several genes, including the oncogenic let-7C miRNA by PPs, was observed between Wt and hPPARαPAC mice that may contribute to the inherent difference between mouse and hPPARα in activation of hepatocellular proliferation. The hPPARαPAC mouse model provides an in vivo platform to investigate the species difference mediated by PPARα and an ideal model for human risk assessment PPs exposure.
doi:10.1093/toxsci/kfm206
PMCID: PMC2197159  PMID: 17690133
humanized; PAC; PPARα; hepatomegaly; peroxisome proliferators
6.  Sorting out the roles of PPARα in energy metabolism and vascular homeostasis 
Journal of Clinical Investigation  2006;116(3):571-580.
PPARα is a nuclear receptor that regulates liver and skeletal muscle lipid metabolism as well as glucose homeostasis. Acting as a molecular sensor of endogenous fatty acids (FAs) and their derivatives, this ligand-activated transcription factor regulates the expression of genes encoding enzymes and transport proteins controlling lipid homeostasis, thereby stimulating FA oxidation and improving lipoprotein metabolism. PPARα also exerts pleiotropic antiinflammatory and antiproliferative effects and prevents the proatherogenic effects of cholesterol accumulation in macrophages by stimulating cholesterol efflux. Cellular and animal models of PPARα help explain the clinical actions of fibrates, synthetic PPARα agonists used to treat dyslipidemia and reduce cardiovascular disease and its complications in patients with the metabolic syndrome. Although these preclinical studies cannot predict all of the effects of PPARα in humans, recent findings have revealed potential adverse effects of PPARα action, underlining the need for further study. This Review will focus on the mechanisms of action of PPARα in metabolic diseases and their associated vascular pathologies.
doi:10.1172/JCI27989
PMCID: PMC1386122  PMID: 16511589
7.  Conditional Expression of Human PPARδ and a Dominant Negative Variant of hPPARδ In Vivo 
PPAR Research  2012;2012:216817.
The nuclear receptor, NR1C2 or peroxisome proliferator-activated receptor (PPAR)-δ, is ubiquitously expressed and important for placental development, fatty acid metabolism, wound healing, inflammation, and tumour development. PPARδ has been hypothesized to function as both a ligand activated transcription factor and a repressor of transcription in the absence of agonist. In this paper, treatment of mice conditionally expressing human PPARδ with GW501516 resulted in a marked loss in body weight that was not evident in nontransgenic animals or animals expressing a dominant negative derivative of PPARδ. Expression of either functional or dominant negative hPPARδ blocked bezafibrate-induced PPARα-dependent hepatomegaly and blocked the effect of bezafibrate on the transcription of PPARα target genes. These data demonstrate, for the first time, that PPARδ could inhibit the activation of PPARα in vivo and provide novel models for the investigation of the role of PPARδ in pathophysiology.
doi:10.1155/2012/216817
PMCID: PMC3324915  PMID: 22550474
8.  Anticancer Properties of PPARα-Effects on Cellular Metabolism and Inflammation 
PPAR Research  2008;2008:930705.
Peroxisome proliferator-activated receptors (PPARs) have lately attracted much attention as therapeutic targets. Previously, PPAR ligands were associated with the treatment of diabetes, hyperlipidemia and cardiovascular diseases, as they modulate the expression of genes regulating glucose and lipid metabolism. Recently, PPAR ligands have been also considered as potential anticancer agents, with relatively low systemic toxicity. The emerging evidence for antiproliferative, proapoptotic, antiinflammatory and potential antimetastatic properties of PPARα ligands prompted us to discuss possible roles of PPARα in tumor suppression. PPARα activation can target cancer cells energy balance by blocking fatty acid synthesis and by promoting fatty acid β-oxidation. In the state of limited nutrient availability, frequently presents in the tumor microenvironment, PPARα cooperates with AMP-dependent protein kinase in: (i) repressing oncogenic Akt activity, (ii) inhibiting cell proliferation, and (iii) forcing glycolysis-dependent cancer cells into “metabolic catastrophe.” Other potential anticancer effects of PPARα include suppression of inflammation, and upregulation of uncoupling proteins (UCPs), which attenuates mitochondrial reactive oxygen species production and cell proliferation. In conclusion, there are strong premises that the low-toxic and well-tolerated PPAR ligands should be considered as new therapeutic agents to fight disseminating cancer, which represents the major challenge for modern medicine and basic research.
doi:10.1155/2008/930705
PMCID: PMC2396219  PMID: 18509489
9.  Comprehensive Analysis of PPARα-Dependent Regulation of Hepatic Lipid Metabolism by Expression Profiling 
PPAR Research  2007;2007:26839.
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.
doi:10.1155/2007/26839
PMCID: PMC2233741  PMID: 18288265
10.  The Coactivator PGC-1 Cooperates with Peroxisome Proliferator-Activated Receptor α in Transcriptional Control of Nuclear Genes Encoding Mitochondrial Fatty Acid Oxidation Enzymes 
Molecular and Cellular Biology  2000;20(5):1868-1876.
Peroxisome proliferator-activated receptor α (PPARα) plays a key role in the transcriptional control of genes encoding mitochondrial fatty acid β-oxidation (FAO) enzymes. In this study we sought to determine whether the recently identified PPAR gamma coactivator 1 (PGC-1) is capable of coactivating PPARα in the transcriptional control of genes encoding FAO enzymes. Mammalian cell cotransfection experiments demonstrated that PGC-1 enhanced PPARα-mediated transcriptional activation of reporter plasmids containing PPARα target elements. PGC-1 also enhanced the transactivation activity of a PPARα-Gal4 DNA binding domain fusion protein. Retroviral vector-mediated expression studies performed in 3T3-L1 cells demonstrated that PPARα and PGC-1 cooperatively induced the expression of PPARα target genes and increased cellular palmitate oxidation rates. Glutathione S-transferase “pulldown” studies revealed that in contrast to the previously reported ligand-independent interaction with PPARγ, PGC-1 binds PPARα in a ligand-influenced manner. Protein-protein interaction studies and mammalian cell hybrid experiments demonstrated that the PGC-1–PPARα interaction involves an LXXLL domain in PGC-1 and the PPARα AF2 region, consistent with the observed ligand influence. Last, the PGC-1 transactivation domain was mapped to within the NH2-terminal 120 amino acids of the PGC-1 molecule, a region distinct from the PPARα interacting domains. These results identify PGC-1 as a coactivator of PPARα in the transcriptional control of mitochondrial FAO capacity, define separable PPARα interaction and transactivation domains within the PGC-1 molecule, and demonstrate that certain features of the PPARα–PGC-1 interaction are distinct from that of PPARγ–PGC-1.
PMCID: PMC85369  PMID: 10669761
11.  The Effect of PPARα, PPARδ, PPARγ, and PPARpan Agonists on Body Weight, Body Mass, and Serum Lipid Profiles in Diet-Induced Obese AKR/J Mice 
PPAR Research  2007;2007:97125.
Activation of peroxisome proliferator-activated receptor (PPAR) α, δ, and γ subtypes increases expression of genes involved in fatty acid transport and oxidation and alters adiposity in animal models of obesity and type-2 diabetes. PPARpan agonists which activate all three receptor subtypes have antidiabetic activity in animal models without the weight gain associated with selective PPARγ agonists. Herein we report the effects of selective PPAR agonists (GW9578, a PPARα agonist, GW0742, a PPARδ agonist, GW7845, a PPARγ agonist), combination of PPARα and δ agonists, and PPARpan (PPARα/γ/δ) activators (GW4148 or GW9135) on body weight (BW), body composition, food consumption, fatty acid oxidation, and serum chemistry of diet-induced obese AKR/J mice. PPARα or PPARδ agonist treatment induced a slight decrease in fat mass (FM) while a PPARγ agonist increased BW and FM commensurate with increased food consumption. The reduction in BW and food intake after cotreatment with PPARα and δ agonists appeared to be synergistic. GW4148, a PPARpan agonist, induced a significant and sustained reduction in BW and FM similar to an efficacious dose of rimonabant, an antiobesity compound. GW9135, a PPARpan agonist with weak activity at PPARδ, induced weight loss initially followed by rebound weight gain reaching vehicle control levels by the end of the experiment. We conclude that PPARα and PPARδ activations are critical to effective weight loss induction. These results suggest that the PPARpan compounds may be expected to maintain the beneficial insulin sensitization effects of a PPARγ agonist while either maintaining weight or producing weight loss.
doi:10.1155/2007/97125
PMCID: PMC1940322  PMID: 17710237
12.  Expression of PPARα modifies fatty acid effects on insulin secretion in uncoupling protein-2 knockout mice 
Aims/hypothesis
In uncoupling protein-2 (UCP2) knockout (KO) mice, protection of beta cells from fatty acid exposure is dependent upon transcriptional events mediated by peroxisome proliferator-activated receptor-α (PPARα).
Methods
PPARα expression was reduced in isolated islets from UCP2KO and wild-type (WT) mice with siRNA for PPARα (siPPARα) overnight. Some islets were also cultured with oleic or palmitic acid, then glucose stimulated insulin secretion (GSIS) was measured. Expression of genes was examined by quantitative RT-PCR or immunoblotting. PPARα activation was assessed by oligonucleotide consensus sequence binding.
Results
siPPARα treatment reduced PPARα protein expression in KO and WT islets by >85%. In siPPARα-treated UCP2KO islets, PA but not OA treatment significantly decreased the insulin response to 16.5 mM glucose. In WT islets, siPPARα treatment did not modify GSIS in PA and OA exposed groups. In WT islets, PA treatment significantly increased UCP2 mRNA and protein expression. Both PA and OA treatment significantly increased PPARα expression in UCP2KO and WT islets but OA treatment augmented PPARα protein expression only in UCP2KO islets (p < 0.05). PA treatment induced carnitine palmitoyltransferase I, acyl CoA oxidase and malonyl CoA decarboxylase mRNA in UCP2KO islets.
Conclusion
These data show that the negative effect of saturated fatty acid on GSIS is mediated by PPARα/UCP2. Knockout of UCP2 protects beta-cells from PA exposure. However, in the absence of both UCP2 and PPARα even a short exposure (24 h) to PA significantly impairs GSIS.
doi:10.1186/1743-7075-4-6
PMCID: PMC1828157  PMID: 17341307
13.  Comparative Analysis of Gene Regulation by the Transcription Factor PPARα between Mouse and Human 
PLoS ONE  2009;4(8):e6796.
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.
doi:10.1371/journal.pone.0006796
PMCID: PMC2729378  PMID: 19710929
14.  Profiling of promoter occupancy by PPARα in human hepatoma cells via ChIP-chip analysis 
Nucleic Acids Research  2010;38(9):2839-2850.
The transcription factor peroxisome proliferator-activated receptor α (PPARα) is an important regulator of hepatic lipid metabolism. While PPARα is known to activate transcription of numerous genes, no comprehensive picture of PPARα binding to endogenous genes has yet been reported. To fill this gap, we performed Chromatin immunoprecipitation (ChIP)-chip in combination with transcriptional profiling on HepG2 human hepatoma cells treated with the PPARα agonist GW7647. We found that GW7647 increased PPARα binding to 4220 binding regions. GW7647-induced binding regions showed a bias around the transcription start site and most contained a predicted PPAR binding motif. Several genes known to be regulated by PPARα, such as ACOX1, SULT2A1, ACADL, CD36, IGFBP1 and G0S2, showed GW7647-induced PPARα binding to their promoter. A GW7647-induced PPARα-binding region was also assigned to SREBP-targets HMGCS1, HMGCR, FDFT1, SC4MOL, and LPIN1, expression of which was induced by GW7647, suggesting cross-talk between PPARα and SREBP signaling. Our data furthermore demonstrate interaction between PPARα and STAT transcription factors in PPARα-mediated transcriptional repression, and suggest interaction between PPARα and TBP, and PPARα and C/EBPα in PPARα-mediated transcriptional activation. Overall, our analysis leads to important new insights into the mechanisms and impact of transcriptional regulation by PPARα in human liver and highlight the importance of cross-talk with other transcription factors.
doi:10.1093/nar/gkq012
PMCID: PMC2875002  PMID: 20110263
15.  PPARα: energy combustion, hypolipidemia, inflammation and cancer  
The peroxisome proliferator-activated receptor α (PPARα, or NR1C1) is a nuclear hormone receptor activated by a structurally diverse array of synthetic chemicals known as peroxisome proliferators. Endogenous activation of PPARα in liver has also been observed in certain gene knockout mouse models of lipid metabolism, implying the existence of enzymes that either generate (synthesize) or degrade endogenous PPARα agonists. For example, substrates involved in fatty acid oxidation can function as PPARα ligands. PPARα serves as a xenobiotic and lipid sensor to regulate energy combustion, hepatic steatosis, lipoprotein synthesis, inflammation and liver cancer. Mainly, PPARα modulates the activities of all three fatty acid oxidation systems, namely mitochondrial and peroxisomal β-oxidation and microsomal ω-oxidation, and thus plays a key role in energy expenditure. Sustained activation of PPARα by either exogenous or endogenous agonists leads to the development of hepatocellular carcinoma resulting from sustained oxidative and possibly endoplasmic reticulum stress and liver cell proliferation. PPARα requires transcription coactivator PPAR-binding protein (PBP)/mediator subunit 1(MED1) for its transcriptional activity.
doi:10.1621/nrs.08002
PMCID: PMC2858266  PMID: 20414453
16.  Tissue-Specific 5′ Heterogeneity of PPARα Transcripts and Their Differential Regulation by Leptin 
PLoS ONE  2013;8(6):e67483.
The genes encoding nuclear receptors comprise multiple 5′untranslated exons, which give rise to several transcripts encoding the same protein, allowing tissue-specific regulation of expression. Both human and mouse peroxisome proliferator activated receptor (PPAR) α genes have multiple promoters, although their function is unknown. Here we have characterised the rat PPARα promoter region and have identified three alternative PPARα transcripts, which have different transcription start sites owing to the utilisation of distinct first exons. Moreover these alternative PPARα transcripts were differentially expressed between adipose tissue and liver. We show that while the major adipose (P1) and liver (P2) transcripts were both induced by dexamethasone, they were differentially regulated by the PPARα agonist, clofibric acid, and leptin. Leptin had no effect on the adipose-specific P1 transcript, but induced liver-specific P2 promoter activity via a STAT3/Sp1 mechanism. Moreover in Wistar rats, leptin treatment between postnatal day 3–13 led to an increase in P2 but not P1 transcription in adipose tissue which was sustained into adulthood. This suggests that the expression of the alternative PPARα transcripts are in part programmed by early life exposure to leptin leading to persistent change in adipose tissue fatty acid metabolism through specific activation of a quiescent PPARα promoter. Such complexity in the regulation of PPARα may allow the expression of PPARα to be finely regulated in response to environmental factors.
doi:10.1371/journal.pone.0067483
PMCID: PMC3692471  PMID: 23825665
17.  Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARα, β/δ, and γ 
Journal of Clinical Investigation  2004;114(11):1564-1576.
PPARα, β/δ, and γ regulate genes involved in the control of lipid metabolism and inflammation and are expressed in all major cell types of atherosclerotic lesions. In vitro studies have suggested that PPARs exert antiatherogenic effects by inhibiting the expression of proinflammatory genes and enhancing cholesterol efflux via activation of the liver X receptor–ABCA1 (LXR-ABCA1) pathway. To investigate the potential importance of these activities in vivo, we performed a systematic analysis of the effects of PPARα, β, and γ agonists on foam-cell formation and atherosclerosis in male LDL receptor–deficient (LDLR–/–) mice. Like the PPARγ agonist, a PPARα-specific agonist strongly inhibited atherosclerosis, whereas a PPARβ-specific agonist failed to inhibit lesion formation. In concert with their effects on atherosclerosis, PPARα and PPARγ agonists, but not the PPARβ agonist, inhibited the formation of macrophage foam cells in the peritoneal cavity. Unexpectedly, PPARα and PPARγ agonists inhibited foam-cell formation in vivo through distinct ABCA1-independent pathways. While inhibition of foam-cell formation by PPARα required LXRs, activation of PPARγ reduced cholesterol esterification, induced expression of ABCG1, and stimulated HDL-dependent cholesterol efflux in an LXR-independent manner. In concert, these findings reveal receptor-specific mechanisms by which PPARs influence macrophage cholesterol homeostasis. In the future, these mechanisms may be exploited pharmacologically to inhibit the development of atherosclerosis.
doi:10.1172/JCI200418730
PMCID: PMC529277  PMID: 15578089
18.  A Newly Identified CG301269 Improves Lipid and Glucose Metabolism Without Body Weight Gain Through Activation of Peroxisome Proliferator–Activated Receptor α and γ 
Diabetes  2011;60(2):496-506.
OBJECTIVE
Peroxisome proliferator–activated receptor (PPAR)-α/γ dual agonists have been developed to alleviate metabolic disorders. However, several PPARα/γ dual agonists are accompanied with unwanted side effects, including body weight gain, edema, and tissue failure. This study investigated the effects of a novel PPARα/γ dual agonist, CG301269, on metabolic disorders both in vitro and in vivo.
RESEARCH DESIGN AND METHODS
Function of CG301269 as a PPARα/γ dual agonist was assessed in vitro by luciferase reporter assay, mammalian one-hybrid assay, and analyses of PPAR target genes. In vitro profiles on fatty acid oxidation and inflammatory responses were acquired by fatty acid oxidation assay and quantitative (q)RT-PCR of proinflammatory genes. In vivo effect of CG301269 was examined in db/db mice. Total body weight and various tissue weights were measured, and hepatic lipid profiles were analyzed. Systemic glucose and insulin tolerance were measured, and the in vivo effect of CG301269 on metabolic genes and proinflammatory genes was examined by qRT-PCR.
RESULTS
CG301269 selectively stimulated the transcriptional activities of PPARα and PPARγ. CG301269 enhanced fatty acid oxidation in vitro and ameliorated insulin resistance and hyperlipidemia in vivo. In db/db mice, CG301269 reduced inflammatory responses and fatty liver, without body weight gain.
CONCLUSIONS
We demonstrate that CG301269 exhibits beneficial effects on glucose and lipid metabolism by simultaneous activation of both PPARα and PPARγ. Our data suggest that CG301269 would be a potential lead compound against obesity and related metabolic disorders.
doi:10.2337/db09-1145
PMCID: PMC3028349  PMID: 21270261
19.  Regulation of Peroxisome Proliferator-Activated Receptors by E6-Associated Protein 
PPAR Research  2008;2008:746935.
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors (NRs) that regulate genes involved in lipid and glucose metabolism. PPAR activity is regulated by interactions with cofactors and of interest are cofactors with ubiquitin ligase activity. The E6-associated protein (E6-AP) is an E3 ubiquitin ligase that affects the activity of other NRs, although its effects on PPARs have not been examined. E6-AP inhibited the ligand-independent transcriptional activity of PPARα and PPARβ, with marginal effects on PPARγ, and decreased basal mRNA levels of PPARα target genes. Inhibition of PPARα activity required the ubiquitin ligase function of E6-AP, but occurred in a proteasome-independent manner. PPARα interacted with E6-AP, and in mice treated with PPARα agonist clofibrate, mRNA and protein levels of E6-AP were increased in wildtype, but not in PPARα null mice, indicating a PPARα-dependent regulation. These studies suggest coordinate regulation of E6-AP and PPARα, and contribute to our understanding of the role of PPARs in cellular metabolism.
doi:10.1155/2008/746935
PMCID: PMC2605849  PMID: 19107217
20.  A Comparative Study of Mouse Hepatic and Intestinal Gene Expression Profiles under PPARα Knockout by Gene Set Enrichment Analysis 
PPAR Research  2011;2011:629728.
Gene expression profiling of PPARα has been used in several studies, but fewer studies went further to identify the tissue-specific pathways or genes involved in PPARα activation in genome-wide. Here, we employed and applied gene set enrichment analysis to two microarray datasets both PPARα related respectively in mouse liver and intestine. We suggested that the regulatory mechanism of PPARα activation by WY14643 in mouse small intestine is more complicated than in liver due to more involved pathways. Several pathways were cancer-related such as pancreatic cancer and small cell lung cancer, which indicated that PPARα may have an important role in prevention of cancer development. 12 PPARα dependent pathways and 4 PPARα independent pathways were identified highly common in both liver and intestine of mice. Most of them were metabolism related, such as fatty acid metabolism, tryptophan metabolism, pyruvate metabolism with regard to PPARα regulation but gluconeogenesis and propanoate metabolism independent of PPARα regulation. Keratan sulfate biosynthesis, the pathway of regulation of actin cytoskeleton, the pathways associated with prostate cancer and small cell lung cancer were not identified as hepatic PPARα independent but as WY14643 dependent ones in intestinal study. We also provided some novel hepatic tissue-specific marker genes.
doi:10.1155/2011/629728
PMCID: PMC3147148  PMID: 21811494
21.  Increased Proximal tubule PPARα in KAP2-PPARα Tg mice confers protection during acute kidney injury 
Kidney international  2009;76(10):1049-1062.
In the present study we have generated transgenic mice that express Peroxisome Proliferator-Activated Receptor-alpha (PPARα) in the proximal tubule under the control of kidney androgen-induced protein (KAP2) promoter. Up-regulation of proximal tubule PPARα expression by testosterone treatment in KAP2-PPARα female Transgenic (Tg) mice ameliorated kidney function from cisplatin (CP) or ischemia-reperfusion (I/R)-induced acute kidney injury (AKI). In addition, CP and I/R-mediated inhibition of fatty acid oxidation, and CP-mediated reduced expression of mitochondrial genes associated with oxidative phosphorylation, mitochondrial DNA, fatty acid metabolism, and tricarboxylic acid cycle were ameliorated in KAP2-PPARα Tg mice treated with testosterone. Similarly, CP and I/R-mediated increased in 4-hydroxy-2-hexenal (HHE).-derived lipid peroxidation products were reduced, and CP and I/R-induced necrosis of the proximal tubule S3 segment was reduced. These results suggest an important function of proximal tubule PPARα as a metabolic sensor, and demonstrate that its increased expression in KAP2-PPARα Tg mice, without the use of exogenous ligand, is sufficient to protect kidney function and morphology, and to prevent abnormalities in lipid metabolism associated with CP or I/R-induced AKI.
doi:10.1038/ki.2009.330
PMCID: PMC3244273  PMID: 19710628
22.  Differences in Transcriptional Activation by the Two Allelic (L162V Polymorphic) Variants of PPARα after Omega-3 Fatty Acids Treatment 
PPAR Research  2009;2009:369602.
Omega-3 fatty acids (FAs) have the potential to regulate gene expression via the peroxisome proliferator-activated receptor α (PPARα); therefore, genetic variations in this gene may impact its transcriptional activity on target genes. It is hypothesized that the transcriptional activity by wild-type L162-PPARα is enhanced to a greater extent than the mutated variant (V162-PPARα) in the presence of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) or a mixture of EPA:DHA. To examine the functional difference of the two allelic variants on receptor activity, transient co-transfections were performed in human hepatoma HepG2 cells activated with EPA, DHA and EPA:DHA mixtures. Results indicate that the addition of EPA or DHA demonstrate potential to increase the transcriptional activity by PPARα with respect to basal level in both variants. Yet, the EPA:DHA mixtures enhanced the transcriptional activity to a greater extent than individual FAs indicating possible additive effects of EPA and DHA. Additionally, the V162 allelic form of PPARα demonstrated consistently lower transcriptional activation when incubated with EPA, DHA or EPA:DHA mixtures than, the wild-type variant. In conclusion, both allelic variants of the PPARα L162V are activated by omega-3 FAs; however, the V162 allelic form displays a lower transcriptional activity than the wild-type variant.
doi:10.1155/2009/369602
PMCID: PMC2649533  PMID: 19266045
23.  Omega-3 fatty acids regulate gene expression levels differently in subjects carrying the PPARα L162V polymorphism 
Genes & Nutrition  2009;4(3):199-205.
Omega-3 fatty acids (FAs) are natural ligands of the peroxisome proliferator-activated receptor-α (PPARα), a nuclear receptor that modulates expression levels of genes involved in lipid metabolism. The L162V polymorphism of the PPARα gene is associated with a deteriorated metabolic profile. We postulate that subjects carrying the PPARα-V162 allele exhibit differences in the expression of PPARα and its target genes after incubation with omega-3 FAs compared with L162 homozygotes. Peripheral blood monocytes from six men carrying the PPARα-V162 allele paired for age and for body mass index with six L162 homozygotes were differentiated into macrophages and activated with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), or mixtures of EPA:DHA. Data demonstrates that gene expression levels of PPARα and apolipoprotein AI (APOA1) were significantly lower for carriers of the PPARα-V162 allele compared to L162 homozygotes after the addition of DHA and a mixture of EPA:DHA. Additionally, lipoprotein lipase (LPL) gene expression displayed a tendency to be lower in the PPARα L162V polymorphism subgroup after the addition of a mixture of EPA:DHA. Consequently, individuals carrying the PPARα-V162 allele may demonstrate inferior improvements in their lipid profile due to alterations in gene expression rates in response to omega-3 FA supplementation.
doi:10.1007/s12263-009-0129-2
PMCID: PMC2745745  PMID: 19585164
Eicosapentaenoic acid; Docosahexaenoic acid; PPARα; Lipoprotein lipase; Apolipoprotein AI; Triglycerides
24.  Activation of peroxisome proliferator activated receptor alpha ameliorates ethanol induced steatohepatitis in mice 
Background
Peroxisome proliferator activated receptor alpha (PPARα) regulates lipids metabolism and inhibits inflammatory response. However, the role of PPARα in alcoholic liver disease is largely unknown. We aim to elucidate the effect and the molecular basis of PPARα in ethanol induced hepatic injury in mice.
Results
C57BL/6J mice fed with 4% ethanol-containing Lieber-DeCarli liquid diet for 12 weeks exhibited hepatocyte steatosis, necrosis and inflammatory infiltration, accompanied with elevated serum alanine aminotransferase (ALT) and aspartic transaminase (AST) levels, decreased hepatic expression of PPARα, lipids oxidation promoting genes and anti-inflammatory factors, as well as enhanced hepatic expression of fatty acids synthesis promoting genes and pro-inflammatory cytokines. Induction of PPARα by PPARα agonist WY14643 treatment for 2 weeks ameliorated the severity of liver injury and restored expression of genes altered by ethanol treatment. However, administration of PPARα antagonist GW6471 for 2 weeks promoted the inflammatory response.
Conclusions
The present study provided the evidence for the protective role of PPARα in ameliorating ethanol induced liver injury through modulation of the genes related to lipid metabolism and inflammatory response.
doi:10.1186/1476-511X-10-246
PMCID: PMC3278384  PMID: 22208561
Peroxisome proliferator activated receptor alpha; ethanol; steatohepatitis; animal experiment
25.  PPARα in Obesity: Sex Difference and Estrogen Involvement 
PPAR Research  2010;2010:584296.
Peroxisome proliferator-activated receptor α (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, PPARα regulates the transcription of a number of genes critical for lipid and lipoprotein metabolism. PPARα activators 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 PPARα ligand 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 PPARα target genes, and these processes may be mediated by inhibiting the coactivator recruitment of PPARα. Thus, it is likely that PPARα functions on obesity may be enhanced in estrogen-deficient states.
doi:10.1155/2010/584296
PMCID: PMC2943125  PMID: 20871824

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