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Trends in Cell Biology Aug 2021Peroxisomes are involved in multiple metabolic processes, including fatty acid oxidation, ether lipid synthesis, and reactive oxygen species (ROS) metabolism. Recent... (Review)
Review
Peroxisomes are involved in multiple metabolic processes, including fatty acid oxidation, ether lipid synthesis, and reactive oxygen species (ROS) metabolism. Recent studies suggest that peroxisomes are critical mediators of cellular responses to various forms of stress, including oxidative stress, hypoxia, starvation, cold exposure, and noise. As dynamic organelles, peroxisomes can modulate their proliferation, morphology, and movement within cells, and engage in crosstalk with other organelles in response to external cues. Although peroxisome-derived hydrogen peroxide has a key role in cellular signaling related to stress, emerging studies suggest that other products of peroxisomal metabolism, such as acetyl-CoA and ether lipids, are also important for metabolic adaptation to stress. Here, we review molecular mechanisms through which peroxisomes regulate metabolic and environmental stress.
Topics: Lipid Metabolism; Oxidation-Reduction; Oxidative Stress; Peroxisomes; Reactive Oxygen Species
PubMed: 33674166
DOI: 10.1016/j.tcb.2021.02.005 -
International Journal of Molecular... Jul 2020Mitochondria and peroxisomes are ubiquitous subcellular organelles that are highly dynamic and possess a high degree of plasticity. These organelles proliferate through... (Review)
Review
Mitochondria and peroxisomes are ubiquitous subcellular organelles that are highly dynamic and possess a high degree of plasticity. These organelles proliferate through division of pre-existing organelles. Studies on yeast, mammalian cells, and unicellular algae have led to a surprising finding that mitochondria and peroxisomes share the components of their division machineries. At the heart of the mitochondrial and peroxisomal division machineries is a GTPase dynamin-like protein, Dnm1/Drp1, which forms a contractile ring around the neck of the dividing organelles. During division, Dnm1/Drp1 functions as a motor protein and constricts the membrane. This mechanochemical work is achieved by utilizing energy from GTP hydrolysis. Over the last two decades, studies have focused on the structure and assembly of Dnm1/Drp1 molecules around the neck. However, the regulation of GTP during the division of mitochondrion and peroxisome is not well understood. Here, we review the current understanding of Dnm1/Drp1-mediated divisions of mitochondria and peroxisomes, exploring the mechanisms of GTP regulation during the Dnm1/Drp1 function, and provide new perspectives on their potential contribution to mitochondrial and peroxisomal biogenesis.
Topics: Animals; Cell Division; Dynamins; GTP Phosphohydrolases; Humans; Mitochondria; Mitochondrial Dynamics; Mitochondrial Proteins; Molecular Motor Proteins; Peroxisomes; Saccharomyces cerevisiae Proteins
PubMed: 32751702
DOI: 10.3390/ijms21155452 -
International Journal of Molecular... Jun 2018Peroxisome proliferator activated receptors (PPARs) are a class of ligand-activated transcription factors, belonging to the superfamily of receptors for steroid and... (Review)
Review
Peroxisome proliferator activated receptors (PPARs) are a class of ligand-activated transcription factors, belonging to the superfamily of receptors for steroid and thyroid hormones, retinoids, and vitamin D. PPARs control the expression of several genes connected with carbohydrate and lipid metabolism, and it has been demonstrated that PPARs play important roles in determining neural stem cell (NSC) fate. Lipogenesis and aerobic glycolysis support the rapid proliferation during neurogenesis, and specific roles for PPARs in the control of different phases of neurogenesis have been demonstrated. Understanding the changes in metabolism during neuronal differentiation is important in the context of stem cell research, neurodegenerative diseases, and regenerative medicine. In this review, we will discuss pivotal evidence that supports the role of PPARs in energy metabolism alterations during neuronal maturation and neurodegenerative disorders.
Topics: Adaptation, Physiological; Animals; Cell Differentiation; Energy Metabolism; Humans; Neurodegenerative Diseases; Neurogenesis; Neurons; Peroxisome Proliferator-Activated Receptors
PubMed: 29949869
DOI: 10.3390/ijms19071869 -
Frontiers in Pharmacology 2021Atherosclerosis (AS) is the main pathological cause of acute cardiovascular and cerebrovascular diseases, such as acute myocardial infarction and cerebral apoplexy. As... (Review)
Review
Atherosclerosis (AS) is the main pathological cause of acute cardiovascular and cerebrovascular diseases, such as acute myocardial infarction and cerebral apoplexy. As an immune-mediated inflammatory disease, the pathogenesis of AS involves endothelial cell dysfunction, lipid accumulation, foam cell formation, vascular smooth muscle cell (VSMC) migration, and inflammatory factor infiltration. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) plays an important role in lipid metabolism, inflammation, and apoptosis by antagonizing the Wnt/β-catenin pathway and regulating cholesterol efflux and inflammatory factors. Importantly, PPARγ-dependant fatty acid uptake is critical for metabolic programming. Activated PPARγ can exert an anti-atherosclerotic effect by inhibiting the expression of various inflammatory factors, improving endothelial cell function, and restraining the proliferation and migration of VSMCs. Regulatory T cells (Tregs) are the only subset of T lymphocytes that have a completely negative regulatory effect on the autoimmune response. They play a critical role in suppressing excessive immune responses and inflammatory reactions and widely affect AS-associated foam cell formation, plaque rupture, and other processes. Recent studies have shown that PPARγ activation promotes the recruitment of Tregs to reduce inflammation, thereby exerting its anti-atherosclerotic effect. In this review, we provide an overview of the anti-AS roles of PPARγ and Tregs by discussing their pathological mechanisms from the perspective of AS and immune-mediated inflammation, with a focus on basic research and clinical trials of their efficacies alone or in combination in inhibiting atherosclerotic inflammation. Additionally, we explore new ideas for AS treatment and plaque stabilization and establish a foundation for the development of natural PPARγ agonists with Treg recruitment capability.
PubMed: 34658891
DOI: 10.3389/fphar.2021.750078 -
Oncogene Feb 2024Lipid droplets (LDs) are dynamic organelles with a neutral lipid core surrounded by a phospholipid monolayer. Solid tumors exhibit LD accumulation, and it is believed...
Lipid droplets (LDs) are dynamic organelles with a neutral lipid core surrounded by a phospholipid monolayer. Solid tumors exhibit LD accumulation, and it is believed that LDs promote cell survival by providing an energy source during energy deprivation. However, the precise mechanisms controlling LD accumulation and utilization in prostate cancer are not well known. Here, we show peroxisome proliferator-activated receptor α (PPARα) acts downstream of PIM1 kinase to accelerate LD accumulation and promote cell proliferation in prostate cancer. Mechanistically, PIM1 inactivates glycogen synthase kinase 3 beta (GSK3β) via serine 9 phosphorylation. GSK3β inhibition stabilizes PPARα and enhances the transcription of genes linked to peroxisomal biogenesis (PEX3 and PEX5) and LD growth (Tip47). The effects of PIM1 on LD accumulation are abrogated with GW6471, a specific inhibitor for PPARα. Notably, LD accumulation downstream of PIM1 provides a significant survival advantage for prostate cancer cells during nutrient stress, such as glucose depletion. Inhibiting PIM reduces LD accumulation in vivo alongside slow tumor growth and proliferation. Furthermore, TKO mice, lacking PIM isoforms, exhibit suppression in circulating triglycerides. Overall, our findings establish PIM1 as an important regulator of LD accumulation through GSK3β-PPARα signaling axis to promote cell proliferation and survival during nutrient stress.
Topics: Male; Humans; Animals; Mice; Glycogen Synthase Kinase 3 beta; Lipid Droplets; PPAR alpha; Prostatic Neoplasms; Cell Proliferation; Proto-Oncogene Proteins c-pim-1
PubMed: 38097734
DOI: 10.1038/s41388-023-02914-0 -
Journal of Cardiology Oct 2015Peroxisome proliferation-activated receptor gamma (PPARγ) is a nuclear receptor regulating transcription of several genes involved mainly in fatty acid and energy... (Review)
Review
Peroxisome proliferation-activated receptor gamma (PPARγ) is a nuclear receptor regulating transcription of several genes involved mainly in fatty acid and energy metabolism. PPARγ agonists are used as insulin sensitizers for treatment of diabetes. However, according to the results of recent studies, their clinical application can be broadened. Activation of PPARγ has a wide spectrum of biological functions, regulating metabolism, reducing inflammation, influencing the balance of immune cells, inhibiting apoptosis and oxidative stress, and improving endothelial function. These effects appear to be beneficial not only in diabetes and atherosclerosis, but also in a number of other conditions, including cardiovascular surgical interventions. In this review we discuss the role of PPARγ in various conditions associated with cardiovascular risk, including diabetes mellitus, atherosclerosis, and hypertension, and will focus on current applications of PPARγ activators and their therapeutic use. We will also give an overview of the potential use of PPARγ agonists in cardiovascular surgical intervention.
Topics: Atherosclerosis; Cardiovascular Diseases; Cardiovascular Surgical Procedures; Diabetes Mellitus; Humans; Hypertension; PPAR gamma; Risk Factors
PubMed: 26072262
DOI: 10.1016/j.jjcc.2015.05.004 -
Physiological Reviews Jul 2014The peroxisome proliferator-activated receptors, PPARα, PPARβ, and PPARγ, are a family of transcription factors activated by a diversity of molecules including fatty... (Review)
Review
The peroxisome proliferator-activated receptors, PPARα, PPARβ, and PPARγ, are a family of transcription factors activated by a diversity of molecules including fatty acids and fatty acid metabolites. PPARs regulate the transcription of a large variety of genes implicated in metabolism, inflammation, proliferation, and differentiation in different cell types. These transcriptional regulations involve both direct transactivation and interaction with other transcriptional regulatory pathways. The functions of PPARα and PPARγ have been extensively documented mainly because these isoforms are activated by molecules clinically used as hypolipidemic and antidiabetic compounds. The physiological functions of PPARβ remained for a while less investigated, but the finding that specific synthetic agonists exert beneficial actions in obese subjects uplifted the studies aimed to elucidate the roles of this PPAR isoform. Intensive work based on pharmacological and genetic approaches and on the use of both in vitro and in vivo models has considerably improved our knowledge on the physiological roles of PPARβ in various cell types. This review will summarize the accumulated evidence for the implication of PPARβ in the regulation of development, metabolism, and inflammation in several tissues, including skeletal muscle, heart, skin, and intestine. Some of these findings indicate that pharmacological activation of PPARβ could be envisioned as a therapeutic option for the correction of metabolic disorders and a variety of inflammatory conditions. However, other experimental data suggesting that activation of PPARβ could result in serious adverse effects, such as carcinogenesis and psoriasis, raise concerns about the clinical use of potent PPARβ agonists.
Topics: Animals; Cell Differentiation; Cell Proliferation; Humans; Inflammation; Muscles; PPAR-beta
PubMed: 24987006
DOI: 10.1152/physrev.00027.2013 -
Arteriosclerosis, Thrombosis, and... Aug 2016Mitochondrial dysfunction results in high levels of oxidative stress and mitochondrial damage, leading to disruption of endothelial homeostasis. Recent discoveries have... (Review)
Review
Mitochondrial dysfunction results in high levels of oxidative stress and mitochondrial damage, leading to disruption of endothelial homeostasis. Recent discoveries have clarified several pathways, whereby mitochondrial dysregulation contributes to endothelial dysfunction and vascular disease burden. One such pathway centers around peroxisome proliferator receptor-γ coactivator 1α (PGC-1α), a transcriptional coactivator linked to mitochondrial biogenesis and antioxidant defense, among other functions. Although primarily investigated for its therapeutic potential in obesity and skeletal muscle differentiation, the ability of PGC-1α to alter a multitude of cellular functions has sparked interest in its role in the vasculature. Within this context, recent studies demonstrate that PGC-1α plays a key role in endothelial cell and smooth muscle cell regulation through effects on oxidative stress, apoptosis, inflammation, and cell proliferation. The ability of PGC-1α to affect these parameters is relevant to vascular disease progression, particularly in relation to atherosclerosis. Upregulation of PGC-1α can prevent the development of, and even encourage regression of, atherosclerotic lesions. Therefore, PGC-1α is poised to serve as a promising target in vascular disease. This review details recent findings related to PGC-1α in vascular regulation, regulation of PGC-1α itself, the role of PGC-1α in atherosclerosis, and therapies that target this key protein.
Topics: Animals; Apoptosis; Atherosclerosis; Cell Proliferation; Endothelial Cells; Endothelium, Vascular; Gene Expression Regulation; Humans; Inflammation; Mitochondria, Muscle; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Oxidative Stress; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Plaque, Atherosclerotic; Signal Transduction
PubMed: 27312223
DOI: 10.1161/ATVBAHA.116.307123 -
Archives of Toxicology Jan 2018A number of industrial chemicals and therapeutic agents cause liver tumors in rats and mice by activating the nuclear receptor peroxisome proliferator-activated receptor... (Review)
Review
A number of industrial chemicals and therapeutic agents cause liver tumors in rats and mice by activating the nuclear receptor peroxisome proliferator-activated receptor α (PPARα). The molecular and cellular events by which PPARα activators induce rodent hepatocarcinogenesis have been extensively studied elucidating a number of consistent mechanistic changes linked to the increased incidence of liver neoplasms. The weight of evidence relevant to the hypothesized mode of action (MOA) for PPARα activator-induced rodent hepatocarcinogenesis is summarized here. Chemical-specific and mechanistic data support concordance of temporal and dose-response relationships for the key events associated with many PPARα activators. The key events (KE) identified in the MOA are PPARα activation (KE1), alteration in cell growth pathways (KE2), perturbation of hepatocyte growth and survival (KE3), and selective clonal expansion of preneoplastic foci cells (KE4), which leads to the apical event-increases in hepatocellular adenomas and carcinomas (KE5). In addition, a number of concurrent molecular and cellular events have been classified as modulating factors, because they potentially alter the ability of PPARα activators to increase rodent liver cancer while not being key events themselves. These modulating factors include increases in oxidative stress and activation of NF-kB. PPARα activators are unlikely to induce liver tumors in humans due to biological differences in the response of KEs downstream of PPARα activation. This conclusion is based on minimal or no effects observed on cell growth pathways and hepatocellular proliferation in human primary hepatocytes and absence of alteration in growth pathways, hepatocyte proliferation, and tumors in the livers of species (hamsters, guinea pigs and cynomolgus monkeys) that are more appropriate human surrogates than mice and rats at overlapping dose levels. Despite this overwhelming body of evidence and almost universal acceptance of the PPARα MOA and lack of human relevance, several reviews have selectively focused on specific studies that, as discussed, contradict the consensus opinion and suggest uncertainty. In the present review, we systematically address these most germane suggested weaknesses of the PPARα MOA.
Topics: Adverse Outcome Pathways; Animals; Apoptosis; Cell Proliferation; Diethylhexyl Phthalate; Dose-Response Relationship, Drug; Guinea Pigs; Hepatocytes; Humans; Liver; Liver Neoplasms; Macaca fascicularis; Mice; Oxidative Stress; PPAR alpha; Rodentia; Species Specificity
PubMed: 29197930
DOI: 10.1007/s00204-017-2094-7 -
International Journal of Molecular... Oct 2019Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that exert important functions in mediating the pleiotropic effects of diverse exogenous... (Review)
Review
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that exert important functions in mediating the pleiotropic effects of diverse exogenous factors such as physical exercise and food components. Particularly, PPARs act as transcription factors that control the expression of genes implicated in lipid and glucose metabolism, and cellular proliferation and differentiation. In this review, we aim to summarize the recent advancements reported on the effects of lifestyle and food habits on PPAR transcriptional activity in chronic disease.
Topics: Animals; Chronic Disease; Energy Metabolism; Feeding Behavior; Humans; Inflammation; Life Style; Metabolic Syndrome; Peroxisome Proliferator-Activated Receptors; Protein Isoforms
PubMed: 31683535
DOI: 10.3390/ijms20215422