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Cells May 2020Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family. Three different isoforms, PPAR alpha, PPAR beta/delta and PPAR gamma... (Review)
Review
Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family. Three different isoforms, PPAR alpha, PPAR beta/delta and PPAR gamma have been identified. They all form heterodimers with retinoic X receptors to activate or repress downstream target genes dependent on the presence/absence of ligands and coactivators or corepressors. PPARs differ in their tissue expression profile, ligands and specific agonists and antagonists. PPARs attract attention as potential therapeutic targets for a variety of diseases. PPAR alpha and gamma agonists are in clinical use for the treatment of dyslipidemias and diabetes. For both receptors, several clinical trials as potential therapeutic targets for cancer are ongoing. In contrast, PPAR beta/delta has been suggested as a therapeutic target for metabolic syndrome. However, potential risks in the settings of cancer are less clear. A variety of studies have investigated PPAR beta/delta expression or activation/inhibition in different cancer cell models in vitro, but the relevance for cancer growth in vivo is less well documented and controversial. In this review, we summarize critically the knowledge of PPAR beta/delta functions for the different hallmarks of cancer biological capabilities, which interplay to determine cancer growth.
Topics: Animals; Apoptosis; Cellular Senescence; Humans; Neoplasms; Neovascularization, Pathologic; PPAR delta; PPAR-beta
PubMed: 32375405
DOI: 10.3390/cells9051133 -
Journal of Molecular and Cellular... Aug 2022Vascular function is critical for the maintenance of body's homeostasis and is tightly regulated by complex interactions among the vessel wall, hemodynamics,... (Review)
Review
Vascular function is critical for the maintenance of body's homeostasis and is tightly regulated by complex interactions among the vessel wall, hemodynamics, neuro-endocrine factors and metabolic alteration. A variety of cardiovascular risks instigate pro-inflammatory and oxidative responses to impair vascular function, leading to pathological vascular remodeling. Peroxisome proliferator-activated receptor-δ (PPAR-δ) is a ligand-activated nuclear receptor and transcription factor that regulates cell growth and differentiation, metabolism and wound healing. Being expressed in vascular endothelial cells, smooth muscle cells and monocytes, PPAR-δ has pleotropic effects in vascular biology and pathology. In this review, we discussed recent advances regarding the functional roles of PPAR-δ as a critical regulator of vascular homeostasis and as a potential target for the intervention of cardiovascular diseases.
Topics: Endothelial Cells; Gene Expression Regulation; Myocytes, Smooth Muscle; PPAR delta; Receptors, Cytoplasmic and Nuclear
PubMed: 35490844
DOI: 10.1016/j.yjmcc.2022.04.019 -
Nature Reviews. Cardiology Dec 2021Peroxisome proliferator-activated receptor-α (PPARα), PPARδ and PPARγ are transcription factors that regulate gene expression following ligand activation. PPARα... (Review)
Review
Peroxisome proliferator-activated receptor-α (PPARα), PPARδ and PPARγ are transcription factors that regulate gene expression following ligand activation. PPARα increases cellular fatty acid uptake, esterification and trafficking, and regulates lipoprotein metabolism genes. PPARδ stimulates lipid and glucose utilization by increasing mitochondrial function and fatty acid desaturation pathways. By contrast, PPARγ promotes fatty acid uptake, triglyceride formation and storage in lipid droplets, thereby increasing insulin sensitivity and glucose metabolism. PPARs also exert antiatherogenic and anti-inflammatory effects on the vascular wall and immune cells. Clinically, PPARγ activation by glitazones and PPARα activation by fibrates reduce insulin resistance and dyslipidaemia, respectively. PPARs are also physiological master switches in the heart, steering cardiac energy metabolism in cardiomyocytes, thereby affecting pathological heart failure and diabetic cardiomyopathy. Novel PPAR agonists in clinical development are providing new opportunities in the management of metabolic and cardiovascular diseases.
Topics: Cardiovascular Diseases; Humans; PPAR alpha; PPAR delta; PPAR gamma
PubMed: 34127848
DOI: 10.1038/s41569-021-00569-6 -
International Journal of Molecular... Oct 2018Peroxisome proliferator-activated receptor-delta (PPAR-δ), one of three members of the PPAR group in the nuclear receptor superfamily, is a ligand-activated... (Review)
Review
Peroxisome proliferator-activated receptor-delta (PPAR-δ), one of three members of the PPAR group in the nuclear receptor superfamily, is a ligand-activated transcription factor. PPAR-δ regulates important cellular metabolic functions that contribute to maintaining energy balance. PPAR-δ is especially important in regulating fatty acid uptake, transport, and β-oxidation as well as insulin secretion and sensitivity. These salutary PPAR-δ functions in normal cells are thought to protect against metabolic-syndrome-related diseases, such as obesity, dyslipidemia, insulin resistance/type 2 diabetes, hepatosteatosis, and atherosclerosis. Given the high clinical burden these diseases pose, highly selective synthetic activating ligands of PPAR-δ were developed as potential preventive/therapeutic agents. Some of these compounds showed some efficacy in clinical trials focused on metabolic-syndrome-related conditions. However, the clinical development of PPAR-δ agonists was halted because various lines of evidence demonstrated that cancer cells upregulated PPAR-δ expression/activity as a defense mechanism against nutritional deprivation and energy stresses, improving their survival and promoting cancer progression. This review discusses the complex relationship between PPAR-δ in health and disease and highlights our current knowledge regarding the different roles that PPAR-δ plays in metabolism, inflammation, and cancer.
Topics: Animals; Diabetes Mellitus, Type 2; Dyslipidemias; Fatty Liver; Humans; Inflammation; Insulin Resistance; Metabolic Syndrome; Neoplasms; PPAR delta
PubMed: 30373124
DOI: 10.3390/ijms19113339 -
FEBS Letters Jan 2008PPAR delta is the only member in the PPAR subfamily of nuclear receptors that is not a target of current drugs. Animal studies demonstrate PPAR delta activation exerts... (Review)
Review
PPAR delta is the only member in the PPAR subfamily of nuclear receptors that is not a target of current drugs. Animal studies demonstrate PPAR delta activation exerts many favorable effects, including reducing weight gain, increasing skeletal muscle metabolic rate and endurance, improving insulin sensitivity and cardiovascular function and suppressing atherogenic inflammation. These activities stem largely from the ability of PPAR delta to control energy balance, reduce fat burden and protect against lipotoxicity caused by ectopic lipid deposition. Therefore, PPAR delta represents a novel therapeutic target and the development of PPAR delta gonists/modulators may be useful for treating the whole spectrum of metabolic syndrome.
Topics: Humans; Metabolic Syndrome; PPAR delta
PubMed: 18036566
DOI: 10.1016/j.febslet.2007.11.040 -
Neuromolecular Medicine Mar 2021Peroxisome proliferator-activated receptor (PPAR) β/δ belongs to the family of hormone and lipid-activated nuclear receptors, which are involved in metabolism of... (Review)
Review
Peroxisome proliferator-activated receptor (PPAR) β/δ belongs to the family of hormone and lipid-activated nuclear receptors, which are involved in metabolism of long-chain fatty acids, cholesterol, and sphingolipids. Similar to PPAR-α and PPAR-γ, PPAR-β/δ also acts as a transcription factor activated by dietary lipids and endogenous ligands, such as long-chain saturated and polyunsaturated fatty acids, and selected lipid metabolic products, such as eicosanoids, leukotrienes, lipoxins, and hydroxyeicosatetraenoic acids. Together with other PPARs, PPAR-β/δ displays transcriptional activity through interaction with retinoid X receptor (RXR). In general, PPARs have been shown to regulate cell differentiation, proliferation, and development and significantly modulate glucose, lipid metabolism, mitochondrial function, and biogenesis. PPAR-β/δ appears to play a special role in inflammatory processes and due to its proangiogenic and anti-/pro-carcinogenic properties, this receptor has been considered as a therapeutic target for treating metabolic syndrome, dyslipidemia, carcinogenesis, and diabetes. Until now, most studies were carried out in the peripheral organs, and despite of its presence in brain cells and in different brain regions, its role in neurodegeneration and neuroinflammation remains poorly understood. This review is intended to describe recent insights on the impact of PPAR-β/δ and its novel agonists on neuroinflammation and neurodegenerative disorders, including Alzheimer's and Parkinson's, Huntington's diseases, multiple sclerosis, stroke, and traumatic injury. An important goal is to obtain new insights to better understand the dietary and pharmacological regulations of PPAR-β/δ and to find promising therapeutic strategies that could mitigate these neurological disorders.
Topics: Antineoplastic Agents; Brain Ischemia; Brain Neoplasms; Drug Delivery Systems; Endothelial Cells; Glioma; Inflammation; Lipid Metabolism; Neuroblastoma; Neurodegenerative Diseases; Neuroglia; Neurons; Neuroprotective Agents; Oxidative Stress; PPAR delta; PPAR-beta; Retinoid X Receptors; Signal Transduction; Transcription, Genetic
PubMed: 33210212
DOI: 10.1007/s12017-020-08629-9 -
Future Cardiology May 2017The PPARs are a subfamily of three ligand-inducible transcription factors, which belong to the superfamily of nuclear hormone receptors. In mammals, the PPAR subfamily... (Review)
Review
The PPARs are a subfamily of three ligand-inducible transcription factors, which belong to the superfamily of nuclear hormone receptors. In mammals, the PPAR subfamily consists of three members: PPAR-α, PPAR-β/δ and PPAR-γ. PPARs control the expression of a large number of genes involved in metabolic homeostasis, lipid, glucose and energy metabolism, adipogenesis and inflammation. PPARs regulate a large number of metabolic pathways that are implicated in the pathogenesis of metabolic diseases such as metabolic syndrome, Type 2 diabetes mellitus, nonalcoholic fatty liver disease and cardiovascular disease. The aim of this review is to provide up-to-date information about the biochemical and metabolic actions of PPAR-β/δ and PPAR-γ, the therapeutic potential of their agonists currently under clinical development and the cardiovascular disease outcome of clinical trials of PPAR-γ agonists, pioglitazone and rosiglitazone.
Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Humans; Metabolic Syndrome; Non-alcoholic Fatty Liver Disease; PPAR delta; PPAR gamma; PPAR-beta; Pioglitazone; Rosiglitazone; Thiazolidinediones
PubMed: 28581362
DOI: 10.2217/fca-2017-0019 -
The Journal of Clinical Investigation Mar 2006Obesity is a growing threat to global health by virtue of its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively... (Review)
Review
Obesity is a growing threat to global health by virtue of its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X. The nuclear receptors PPARalpha and PPARgamma are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively, and drugs that modulate these receptors are currently in clinical use. More recent work on the less-described PPAR isotype PPARdelta has uncovered a dual benefit for both hypertriglyceridemia and insulin resistance, highlighting the broad potential of PPARdelta in the treatment of metabolic disease. PPARdelta enhances fatty acid catabolism and energy uncoupling in adipose tissue and muscle, and it suppresses macrophage-derived inflammation. Its combined activities in these and other tissues make it a multifaceted therapeutic target for the metabolic syndrome with the potential to control weight gain, enhance physical endurance, improve insulin sensitivity, and ameliorate atherosclerosis.
Topics: Animals; Humans; Lipid Metabolism; Metabolic Syndrome; Muscle, Skeletal; Myocardium; PPAR delta
PubMed: 16511591
DOI: 10.1172/JCI27955 -
Diabetes & Metabolism Feb 2005Peroxisome proliferator-activated receptors (PPAR) mediate some of the transcriptional effects of fatty acids and control many physiological functions, especially in the... (Review)
Review
Peroxisome proliferator-activated receptors (PPAR) mediate some of the transcriptional effects of fatty acids and control many physiological functions, especially in the field of development and metabolism. Three isotypes are known, alpha, gamma, and B/delta. Roles of PPAR alpha and PPARgamma are now quite well-known, particularly since their pharmacologic ligands have been marketed, respectively the lipid-normalizing class of fibrates and the antidiabetic class of thiazolidinediones (glitazones). However, functions of PPARdelta are uncompletely known to date, but some recent data enlight its role in the regulation of fatty acid oxidation in several tissues, such as skeletal muscle and adipose tissue. Overexpression of PPARdelta using a transgenic murine model promotes an increase of muscle oxidative capability. This is accompanied by a redistribution of fatty acid flux, redirected from adipose tissue towards skeletal muscle. Finally, adipose mass is reduced, due to a decreased adipocyte size. These data strongly suggest that PPARdelta play a major role in the metabolic adaptations to western diet characterized by an excessive amount of saturated fat. Considering the metabolic properties of the two other PPAR isotypes, alpha and gamma, it is likely that the three PPAR isotypes have complementary effects in the pathophysiology of obesity and metabolic syndrome. Future therapeutical perspectives in this field should consider combined treatment, adding delta agonists (for all that their safety will be established) to the already available alpha and gamma agonists.
Topics: Animals; Arteriosclerosis; Gene Expression Regulation; Homeostasis; Humans; Lipid Metabolism; Models, Biological; PPAR delta; Transcription, Genetic
PubMed: 15803109
DOI: 10.1016/s1262-3636(07)70162-3 -
International Journal of Medical... 2019Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and its pathogenesis and mechanism are intricate. In the present study, we aimed to...
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and its pathogenesis and mechanism are intricate. In the present study, we aimed to evaluate the role of PPAR δ in LPS associated NAFLD and to investigate the signal transduction pathways underlying PPAR δ treatment in vitro. L02 cells were exposed to palmitic acid (PA) and/or LPS in the absence or presence of PPAR δ inhibition and/or activation. LPS treatment markedly increased lipid deposition, FFA contents, IL-6 and TNF-α levels, and cell apoptosis in PA treatment (NAFLD model). PPAR δ inhibition protects L02 cells against LPS-induced lipidosis and injury. Conversely, the result of PPAR δ activation showed the reverse trend. LPS+PA treatment group significantly decreases the relative expression level of IRS-1, PI3K, AKT, phosphorylation of AKT, TLR-4, MyD88, phosphorylation of IKKα, NF-κB, Bcl-2 and increases the relative expression level of Bax, cleaved caspase 3 and cleaved caspase 8, compared with the cells treated with NAFLD model. PPAR δ inhibition upregulated the related proteins' expression level in insulin resistance and inflammation pathway and downregulated apoptotic relevant proteins. Instead, PPAR δ agonist showed the reverse trend. Our data show that PPAR δ inhibition reduces steatosis, inflammation and apoptosis in LPS-related NAFLD damage, in vitro. PPAR δ may be a potential therapeutic implication for NAFLD.
Topics: Apoptosis; Cells, Cultured; Fatty Liver; Hepatocytes; Humans; Lipidoses; Lipids; Lipopolysaccharides; Liver; Non-alcoholic Fatty Liver Disease; PPAR delta; Palmitic Acid; Protective Agents; RNA, Small Interfering; Signal Transduction; Thiazoles
PubMed: 31839747
DOI: 10.7150/ijms.37677