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International Journal of Molecular... Sep 2021Peroxisome proliferator-activated receptors (PPARs) are ligand-modulated nuclear receptors that play pivotal roles in nutrient sensing, metabolism, and lipid-related... (Review)
Review
Peroxisome proliferator-activated receptors (PPARs) are ligand-modulated nuclear receptors that play pivotal roles in nutrient sensing, metabolism, and lipid-related processes. Correct control of their target genes requires tight regulation of the expression of different PPAR isoforms in each tissue, and the dysregulation of PPAR-dependent transcriptional programs is linked to disorders, such as metabolic and immune diseases or cancer. Several PPAR regulators and PPAR-regulated factors are epigenetic effectors, including non-coding RNAs, epigenetic enzymes, histone modifiers, and DNA methyltransferases. In this review, we examine advances in PPARα and PPARγ-related epigenetic regulation in metabolic disorders, including obesity and diabetes, immune disorders, such as sclerosis and lupus, and a variety of cancers, providing new insights into the possible therapeutic exploitation of PPAR epigenetic modulation.
Topics: Animals; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation; Humans; Immune System Diseases; Metabolic Diseases; Neoplasms; PPAR alpha; PPAR gamma
PubMed: 34638914
DOI: 10.3390/ijms221910573 -
Future Cardiology May 2017This article provides a comprehensive review about the molecular and metabolic actions of PPAR-α. It describes its structural features, ligand specificity, gene... (Review)
Review
This article provides a comprehensive review about the molecular and metabolic actions of PPAR-α. It describes its structural features, ligand specificity, gene transcription mechanisms, functional characteristics and target genes. In addition, recent progress with the use of loss of function and gain of function mouse models in the discovery of diverse biological functions of PPAR-α, particularly in the vascular system and the status of the development of new single, dual, pan and partial PPAR agonists (PPAR modulators) in the clinical management of metabolic diseases are presented. This review also summarizes the clinical outcomes from a large number of clinical trials aimed at evaluating the atheroprotective actions of current clinically used PPAR-α agonists, fibrates and statin-fibrate combination therapy.
Topics: Animals; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Mice; PPAR alpha
PubMed: 28581332
DOI: 10.2217/fca-2016-0059 -
The FEBS Journal Dec 2022Rewiring metabolism to sustain cell growth, division, and survival is the most prominent feature of cancer cells. In particular, dysregulated lipid metabolism in cancer... (Review)
Review
Rewiring metabolism to sustain cell growth, division, and survival is the most prominent feature of cancer cells. In particular, dysregulated lipid metabolism in cancer has received accumulating interest, since lipid molecules serve as cell membrane structure components, secondary signaling messengers, and energy sources. Given the critical role of immune cells in host defense against cancer, recent studies have revealed that immune cells compete for nutrients with cancer cells in the tumor microenvironment and accordingly develop adaptive metabolic strategies for survival at the expense of compromised immune functions. Among these strategies, lipid metabolism reprogramming toward fatty acid oxidation is closely related to the immunosuppressive phenotype of tumor-infiltrated immune cells, including macrophages and dendritic cells. Therefore, it is important to understand the lipid-mediated crosstalk between cancer cells and immune cells in the tumor microenvironment. Peroxisome proliferator-activated receptors (PPARs) consist of a nuclear receptor family for lipid sensing, and one of the family members PPARα is responsible for fatty acid oxidation, energy homeostasis, and regulation of immune cell functions. In this review, we discuss the emerging role of PPARα-associated metabolic-immune regulation in tumor-infiltrated immune cells, and key metabolic events and pathways involved, as well as their influences on antitumor immunity.
Topics: Humans; PPAR alpha; Receptors, Cytoplasmic and Nuclear; Neoplasms; Lipid Metabolism; Fatty Acids; Lipids; Tumor Microenvironment
PubMed: 34480827
DOI: 10.1111/febs.16181 -
The Journal of Neuroscience : the... Nov 2014Cells in injured and inflamed tissues produce a number of proalgesic lipid-derived mediators, which excite nociceptive neurons by activating selective G-protein-coupled... (Review)
Review
Cells in injured and inflamed tissues produce a number of proalgesic lipid-derived mediators, which excite nociceptive neurons by activating selective G-protein-coupled receptors or ligand-gated ion channels. Recent work has shown that these proalgesic factors are counteracted by a distinct group of lipid molecules that lower nociceptor excitability and attenuate nociception in peripheral tissues. Analgesic lipid mediators include endogenous agonists of cannabinoid receptors (endocannabinoids), lipid-amide agonists of peroxisome proliferator-activated receptor-α, and products of oxidative metabolism of polyunsaturated fatty acids via cytochrome P450 and other enzyme pathways. Evidence indicates that these lipid messengers are produced and act at different stages of inflammation and the response to tissue injury, and may be part of a peripheral gating mechanism that regulates the access of nociceptive information to the spinal cord and the brain. Growing knowledge about this peripheral control system may be used to discover safer medicines for pain.
Topics: Animals; Cannabinoid Receptor Agonists; Endocannabinoids; Humans; Hyperalgesia; Inflammation; PPAR alpha; Pain; Receptors, Cannabinoid
PubMed: 25392487
DOI: 10.1523/JNEUROSCI.3475-14.2014 -
Biomolecules May 2022Peroxisome proliferator-activator receptors (PPARs) regulate lipid and glucose metabolism, control inflammatory processes, and modulate several brain functions. Three... (Review)
Review
Peroxisome proliferator-activator receptors (PPARs) regulate lipid and glucose metabolism, control inflammatory processes, and modulate several brain functions. Three PPAR isoforms have been identified, PPARα, PPARβ/δ, and PPARγ, which are expressed in different tissues and cell types. Hereinafter, we focus on PPARα involvement in the pathophysiology of neuropsychiatric and neurodegenerative disorders, which is underscored by PPARα localization in neuronal circuits involved in emotion modulation and stress response, and its role in neurodevelopment and neuroinflammation. A multiplicity of downstream pathways modulated by PPARα activation, including glutamatergic neurotransmission, upregulation of brain-derived neurotrophic factor, and neurosteroidogenic effects, encompass mechanisms underlying behavioral regulation. Modulation of dopamine neuronal firing in the ventral tegmental area likely contributes to PPARα effects in depression, anhedonia, and autism spectrum disorder (ASD). Based on robust preclinical evidence and the initial results of clinical studies, future clinical trials should assess the efficacy of PPARα agonists in the treatment of mood and neurodevelopmental disorders, such as depression, schizophrenia, and ASD.
Topics: Autism Spectrum Disorder; Humans; PPAR alpha; PPAR gamma; Signal Transduction; Transcriptional Activation
PubMed: 35625650
DOI: 10.3390/biom12050723 -
Marine Drugs Jan 2023Peroxisome proliferator-activated receptors α, γ and β/δ (PPARα, PPARγ, and PPARβ/δ) are a family of ligand-activated transcriptional factors belonging to the... (Review)
Review
Peroxisome proliferator-activated receptors α, γ and β/δ (PPARα, PPARγ, and PPARβ/δ) are a family of ligand-activated transcriptional factors belonging to the superfamily of nuclear receptors regulating the expression of genes involved in lipid and carbohydrate metabolism, energy homeostasis, inflammation, and the immune response. For this reason, they represent attractive targets for the treatment of a variety of metabolic diseases and, more recently, for neurodegenerative disorders due to their emerging neuroprotective effects. The degree of activation, from partial to full, along with the selectivity toward the different isoforms, greatly affect the therapeutic efficacy and the safety profile of PPAR agonists. Thus, there is a high interest toward novel scaffolds with proper combinations of activity and selectivity. This review intends to provide an overview of the discovery, optimization, and structure-activity relationship studies on PPAR modulators from marine sources, along with the structural and computational studies that led to their identification and/or elucidation, and rationalization of their mechanisms of action.
Topics: Transcription Factors; PPAR alpha; PPAR gamma; Hypoglycemic Agents
PubMed: 36827130
DOI: 10.3390/md21020089 -
Current Neuropharmacology 2022Peroxisome proliferator-activated receptors (PPARs) activity has significant implications for the development of novel therapeutic modalities against neurodegenerative... (Review)
Review
Peroxisome proliferator-activated receptors (PPARs) activity has significant implications for the development of novel therapeutic modalities against neurodegenerative diseases. Although PPAR-α, PPAR-β/δ, and PPAR-γ nuclear receptor expressions are significantly reported in the brain, their implications in brain physiology and other neurodegenerative diseases still require extensive studies. PPAR signaling can modulate various cell signaling mechanisms involved in the cells contributing to on- and off-target actions selectively to promote therapeutic effects as well as the adverse effects of PPAR ligands. Both natural and synthetic ligands for the PPARα, PPARγ, and PPARβ/δ have been reported. PPARα (WY 14.643) and PPARγ agonists can confer neuroprotection by modulating mitochondrial dynamics through the redox system. The pharmacological effect of these agonists may deliver effective clinical responses by protecting vulnerable neurons from Aβ toxicity in Alzheimer's disease (AD) patients. Therefore, the current review delineated the ligands' interaction with 3D-PPARs to modulate neuroprotection, and also deciphered the efficacy of numerous drugs, viz. Aβ aggregation inhibitors, vaccines, and γ-secretase inhibitors against AD; this review elucidated the role of PPAR and their receptor isoforms in neural systems, and neurodegeneration in human beings. Further, we have substantially discussed the efficacy of PPREs as potent transcription factors in the brain, and the role of PPAR agonists in neurotransmission, PPAR gamma coactivator-1α (PGC-1α) and mitochondrial dynamics in neuroprotection during AD conditions. This review concludes with the statement that the development of novel PPARs agonists may benefit patients with neurodegeneration, mainly AD patients, which may help mitigate the pathophysiology of dementia, subsequently improving overall the patient's quality of life.
Topics: Alzheimer Disease; Drug Repositioning; Humans; Ligands; Mitochondrial Dynamics; Molecular Dynamics Simulation; Neurodegenerative Diseases; Oxidation-Reduction; PPAR alpha; PPAR gamma; Quality of Life; Thiazolidinediones
PubMed: 34751120
DOI: 10.2174/1570159X19666211109141330 -
Poultry Science Aug 2023Cadmium (Cd) is an important environmental pollutant that causes liver damage and induces nonalcoholic fatty liver disease (NAFLD). NAFLD is a fat accumulation disease...
Cadmium (Cd) is an important environmental pollutant that causes liver damage and induces nonalcoholic fatty liver disease (NAFLD). NAFLD is a fat accumulation disease and has significant effects on the body. Melatonin (Mel) is an endogenous protective molecule with antioxidant, anti-inflammatory, antiobesity, and antiaging effects. However, whether Mel can alleviate Cd-induced NAFLD and its mechanism remains unclear. First, in vivo, we found that Mel maintained mitochondrial structure and function, inhibited oxidative stress, and reduced Cd-induced liver injury. In addition, Mel alleviated lipid accumulation in the liver induced by Cd. In this process, Mel inhibits fatty acid production and promotes fatty acid oxidation. Interestingly, Mel regulated PPAR-α expression and alleviated Cd-induced autophagy blockade. In vitro model, the oil Red O staining, and WB results showed that Mel alleviated Cd-induced lipid accumulation. In addition, RAPA was used to activate autophagy to alleviate Cd-induced lipid accumulation, and TG was used to block autophagy flux to aggravate Cd-induced autophagy accumulation. After knocking down PPAR-α, the autophagosome fusion with lysosomes, and autophagic flux was inhibited and increased Cd-induced lipid accumulation. Mel alleviates mitochondrial damage and oxidative stress, and attenuates Cd-induced NAFLD by restoring the expression of PPAR-α and restoring autophagy flux.
Topics: Animals; Non-alcoholic Fatty Liver Disease; Cadmium; Melatonin; Ducks; PPAR alpha; Chickens; Autophagy; Liver; Oxidative Stress; Fatty Acids; Lipids
PubMed: 37343350
DOI: 10.1016/j.psj.2023.102835 -
Theranostics 2022Leucine-rich repeat-containing G protein-coupled receptor 5 () is a target gene of Wnt/β-Catenin which plays a vital role in hepatic development and regeneration....
Leucine-rich repeat-containing G protein-coupled receptor 5 () is a target gene of Wnt/β-Catenin which plays a vital role in hepatic development and regeneration. However, the regulation of gene and the fate of cells in hepatic physiology and pathology are little known. This study aims to clarify the effect of metabolic nuclear receptors on cell fate in liver. We performed cell experiments with primary hepatocytes, Hep 1-6, Hep G2, and Huh 7 cells, and animal studies with wild-type (WT), farnesoid X receptor (FXR) knockout mice, peroxisome proliferator-activated receptor α (PPARα) knockout mice and -Cre; Rosa26-mTmG mice. GW4064 and CDCA were used to activate FXR. And GW7647 or Wy14643 was used for PPARα activation. Regulation of by FXR and PPARα was determined by QRT-PCR, western blot (WB) and RNAscope hybridization (ISH) and immunofluorescence (IF), luciferase reporter assay, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). Diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) diet was used to induce liver injury. Pharmacologic activation of FXR induced expression, whereas activation of PPARα suppressed expression. Furthermore, FXR and PPARα competed for binding to shared site on promoter with opposite transcriptional outputs. DDC diet triggered the transition of cells from resting state to proliferation. FXR activation enhanced cell expansion mainly by symmetric cell division, but PPARα activation prevented cell proliferation along with asymmetric cell division. Our findings unravel the opposite regulatory effects of FXR and PPARα on cell fate in liver under physiological and pathological conditions, which will greatly assist novel therapeutic development targeting nuclear receptors.
Topics: Animals; Leucine; Liver; Mice; Mice, Knockout; PPAR alpha; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled; Signal Transduction; beta Catenin
PubMed: 36168631
DOI: 10.7150/thno.74194 -
International Journal of Molecular... Oct 2021Social behavioral changes, including social isolation or loneliness, increase the risk for stress-related disorders, such as major depressive disorder, posttraumatic...
Social behavioral changes, including social isolation or loneliness, increase the risk for stress-related disorders, such as major depressive disorder, posttraumatic stress disorder (PTSD), and suicide, which share a strong neuroinflammatory etiopathogenetic component. The peroxisome-proliferator activated receptor (PPAR)-α, a newly discovered target involved in emotional behavior regulation, is a ligand-activated nuclear receptor and a transcription factor that, following stimulation by endogenous or synthetic ligands, may induce neuroprotective effects by modulating neuroinflammation, and improve anxiety and depression-like behaviors by enhancing neurosteroid biosynthesis. How stress affects epigenetic mechanisms with downstream effects on inflammation and emotional behavior remains poorly understood. We studied the effects of 4-week social isolation, using a mouse model of PTSD/suicide-like behavior, on hippocampal PPAR-α epigenetic modification. Decreased PPAR-α expression in the hippocampus of socially isolated mice was associated with increased levels of methylated cytosines of PPAR-α gene CpG-rich fragments and deficient neurosteroid biosynthesis. This effect was associated with increased histone deacetylases (HDAC)1, methyl-cytosine binding protein (MeCP)2 and decreased ten-eleven translocator (TET)2 expression, which favor hypermethylation. These alterations were associated with increased TLR-4 and pro-inflammatory markers (e.g., TNF-α,), mediated by NF-κB signaling in the hippocampus of aggressive mice. This study contributes the first evidence of stress-induced brain PPAR-α epigenetic regulation. Social isolation stress may constitute a risk factor for inflammatory-based psychiatric disorders associated with neurosteroid deficits, and targeting epigenetic marks linked to PPAR-α downregulation may offer a valid therapeutic approach.
Topics: Aggression; Animals; Behavior, Animal; Chromatin Assembly and Disassembly; CpG Islands; Disease Models, Animal; Disease Susceptibility; Epigenesis, Genetic; Gene Expression; Hippocampus; Inflammation; Inflammation Mediators; Male; Methylation; Mice; PPAR alpha; Promoter Regions, Genetic; Signal Transduction; Social Isolation; Stress, Psychological
PubMed: 34639019
DOI: 10.3390/ijms221910678