The Peroxisome Proliferator-Activated Receptor β/δ Agonist, GW501516, Regulates the Expression of Genes Involved in Lipid Catabolism and Energy Uncoupling in Skeletal Muscle Cells
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Lipid homeostasis is controlled by the peroxisome proliferator-activated receptors (PPARalpha, -beta/delta, and -gamma) that function as fatty acid-dependent DNA-binding proteins that regulate lipid metabolism. In vitro and in vivo genetic and pharmacological studies have demonstrated PPARalpha regulates lipid catabolism. In contrast, PPARgamma regulates the conflicting process of lipid storage. However, relatively little is known about PPARbeta/delta in the context of target tissues, target genes, lipid homeostasis, and functional overlap with PPARalpha and -gamma. PPARbeta/delta, a very low-density lipoprotein sensor, is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for approximately 40% of total body weight. Skeletal muscle is a metabolically active tissue, and a primary site of glucose metabolism, fatty acid oxidation, and cholesterol efflux. Consequently, it has a significant role in insulin sensitivity, the blood-lipid profile, and lipid homeostasis. Surprisingly, the role of PPARbeta/delta in skeletal muscle has not been investigated. We utilize selective PPARalpha, -beta/delta, -gamma, and liver X receptor agonists in skeletal muscle cells to understand the functional role of PPARbeta/delta, and the complementary and/or contrasting roles of PPARs in this major mass peripheral tissue. Activation of PPARbeta/delta by GW501516 in skeletal muscle cells induces the expression of genes involved in preferential lipid utilization, beta-oxidation, cholesterol efflux, and energy uncoupling. Furthermore, we show that treatment of muscle cells with GW501516 increases apolipoprotein-A1 specific efflux of intracellular cholesterol, thus identifying this tissue as an important target of PPARbeta/delta agonists. Interestingly, fenofibrate induces genes involved in fructose uptake, and glycogen formation. In contrast, rosiglitazone-mediated activation of PPARgamma induces gene expression associated with glucose uptake, fatty acid synthesis, and lipid storage. Furthermore, we show that the PPAR-dependent reporter in the muscle carnitine palmitoyl-transferase-1 promoter is directly regulated by PPARbeta/delta, and not PPARalpha in skeletal muscle cells in a PPARgamma coactivator-1-dependent manner. This study demonstrates that PPARs have distinct roles in skeletal muscle cells with respect to the regulation of lipid, carbohydrate, and energy homeostasis. Moreover, we surmise that PPARbeta/delta agonists would increase fatty acid catabolism, cholesterol efflux, and energy expenditure in muscle, and speculate selective activators of PPARbeta/delta may have therapeutic utility in the treatment of hyperlipidemia, atherosclerosis, and obesity.Retinoid X receptor
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Nutrient and gene interaction is an important aspect of poultry metabolism that determines performance capacity. New technological tools in biochemistry and biotechnology make it possible to explore the molecular base of phenotypic characteristics of poultry production. Fats act as energy deposits in the poultry body and are an essential constituent of animal cell membranes. From a functional standpoint, it has been suggested that ingested lipids change liver fatty acid synthesis and other lipogenic enzymes by regulating mRNA synthesis. Nuclear hormone receptors are ligand-activated transcription factors that control several genes involved in lipid metabolism. The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of transcription factors. Three separate PPAR genes have been identified; they are known as α, δ, and γ. The most important metabolic effect of PPARγ in chicken is its task in adipogenesis. Reviewing the ligands of chicken PPARγ gene can be useful to a better understanding of PPARγ regulatory functions.
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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of the following three subtypes: PPARα, PPARγ, and PPARβ/δ. Activation of PPAR-α reduces triglyceride level and is involved in regulation of energy homeostasis. Activation of PPAR-γ causes insulin sensitization and enhances glucose metabolism, whereas activation of PPAR-β/δ enhances fatty acids metabolism. Thus, PPAR family of nuclear receptors plays a major regulatory role in energy homeostasis and metabolic function. The present review critically analyzes the protective and detrimental effect of PPAR agonists in dyslipidemia, diabetes, adipocyte differentiation, inflammation, cancer, lung diseases, neurodegenerative disorders, fertility or reproduction, pain, and obesity.
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Peroxisome proliferator‐activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand‐activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. The PPAR subfamily comprises of three members, PPAR‐ α , PPAR‐ β and PPAR‐ γ . There is good evidence that ligands of PPAR‐ γ , including certain thiazolinediones, reduce myocardial tissue injury and infarct size. The use of PPAR‐ γ agonists in the treatment of heart failure is, however, controversial. British Journal of Pharmacology (2004) 141 , 1–3. doi: 10.1038/sj.bjp.0705586
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For many tissues fatty acids represent the major source of fuel. In the past few decades it has become evident that in addition to their role as energy substrates, fatty acids also have an important signaling function by modulating transcription of genes. An important group of transcription factors involved in mediating the effects of dietary fatty acids on gene transcription are the Peroxisome Proliferator-Activated Receptors (PPARs). PPARs are members of the superfamily of nuclear hormone receptors and regulate genes involved in numerous important biological processes, ranging from lipid metabolism to inflammation and wound healing. In the liver the dominant PPAR isoform has been show to be PPARα, although PPARβ/δ and PPARγ are expressed in liver as well. The aim of this thesis was to further characterize the role of PPARα and PPARβ/δ in hepatic metabolism and study their activation by fatty acids. Even though PPARα as gene regulator in liver has been well described, a complete overview of its target genes has been lacking so far. By combining several nutrigenomics tools, we succeeded in creating a comprehensive list of PPARα-regulated genes involved in lipid metabolism in liver. Additionally, by using a unique design where mice were fed synthetic triglycerides consisting of one type of fatty acid, we could distinguish between different types of dietary unsaturated fatty acids in their ability to activate PPARα. Although it is well known that PPARα plays an important role in liver during fasting, no direct in vivo evidence exists that circulating free fatty acids are able to ligand activate hepatic PPARα. In our studies, we found that upregulation of gene expression by PPARβ/δ is sensitive to circulating plasma free fatty acids whereas this is not the case for PPARα. Not much is known about the function of PPARβ/δ in the liver. In order to better understand the role of this nuclear receptor, we compared the effects of PPARα and PPARβ/δ deletion on whole genome gene regulation and plasma and liver metabolites. Our results revealed that PPARβ/δ does not mediate an adaptive response to fasting, and pointed to a role for PPARβ/δ in hepatic glucose- and lipoprotein metabolism. In conclusion, this thesis contributes to the important work of mapping the molecular mechanisms dictating lipid metabolism in the liver. By using several nutrigenomics tools, we are able to show that PPARα is a key mediator of the effect of dietary fatty acids on hepatic gene expression. In addition, we better define the roles of PPARα and PPARβ/δ in hepatic metabolism and provide a new concept for functional differentiation between PPARs in liver.
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