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Traffic (Copenhagen, Denmark) Feb 2010Peroxisomes are unique organelles which display properties of autonomous organelles, as they can multiply by fission of pre-existing ones. Peroxisomes, however, can also... (Review)
Review
Peroxisomes are unique organelles which display properties of autonomous organelles, as they can multiply by fission of pre-existing ones. Peroxisomes, however, can also develop from the endoplasmic reticulum (ER). This process has convincingly been shown in peroxisome-deficient yeast cells, upon reintroduction of the corresponding gene. Whether peroxisomes also are formed from the ER in wild-type cells that contain peroxisomes is still under debate. Also, the existence of vesicular transport pathways between peroxisomes and the ER is still unresolved. Several new proteins and pathways that play a role in peroxisome proliferation have been identified in the last few years. A surprising finding was that proteins well known for their function in mitochondrial fission (Fis1, Dnm1) are responsible for peroxisome fission as well. In this contribution we discuss recent advancements in research on peroxisome proliferation.
Topics: Animals; Endoplasmic Reticulum; Humans; Models, Biological; Peroxisomes
PubMed: 20015113
DOI: 10.1111/j.1600-0854.2009.01019.x -
PLoS Genetics Jul 2021The intracellular level of fatty aldehydes is tightly regulated by aldehyde dehydrogenases to minimize the formation of toxic lipid and protein adducts. Importantly, the...
The intracellular level of fatty aldehydes is tightly regulated by aldehyde dehydrogenases to minimize the formation of toxic lipid and protein adducts. Importantly, the dysregulation of aldehyde dehydrogenases has been implicated in neurologic disorder and cancer in humans. However, cellular responses to unresolved, elevated fatty aldehyde levels are poorly understood. Here, we report that ALH-4 is a C. elegans aldehyde dehydrogenase that specifically associates with the endoplasmic reticulum, mitochondria and peroxisomes. Based on lipidomic and imaging analysis, we show that the loss of ALH-4 increases fatty aldehyde levels and reduces fat storage. ALH-4 deficiency in the intestine, cell-nonautonomously induces NHR-49/NHR-79-dependent hypodermal peroxisome proliferation. This is accompanied by the upregulation of catalases and fatty acid catabolic enzymes, as indicated by RNA sequencing. Such a response is required to counteract ALH-4 deficiency since alh-4; nhr-49 double mutant animals are sterile. Our work reveals unexpected inter-tissue communication of fatty aldehyde levels and suggests pharmacological modulation of peroxisome proliferation as a therapeutic strategy to tackle pathology related to excess fatty aldehydes.
Topics: Aldehyde Dehydrogenase; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Gene Expression Regulation; Lipase; Lipid Droplets; Lipolysis; Mutation; Peroxisomes; Receptors, Cytoplasmic and Nuclear
PubMed: 34237064
DOI: 10.1371/journal.pgen.1009635 -
Current Medicinal Chemistry 2010The biological activity of peroxisome proliferators (PPs) is mediated by a class of receptors, known as PPARs (PP-Activated Receptor), belonging to the nuclear receptor... (Review)
Review
The biological activity of peroxisome proliferators (PPs) is mediated by a class of receptors, known as PPARs (PP-Activated Receptor), belonging to the nuclear receptor superfamily. Upon ligand binding, PPARs dimerize with retinoid receptors, translocate to the nucleus, recognize specific PP-responsive elements on DNA and transactivate a number of genes. Several processes are regulated by PPARs, such as mitochondrial and peroxisomal fatty acid uptake and beta-oxidation, inflammation, intracellular lipid trafficking, cell proliferation and death. In addition, PPARs have been proposed to act as tumor suppressors or as tumor promoters, depending on the circumstances. In particular, PPs have been extensively studied for their hepatocarcinogenic action in rodents, most often ascribed to their antiapoptotic action. Recent evidence, however, has been provided about the antiproliferative, proapoptotic, and differentiation-promoting activities displayed by PPAR ligands. The present review will focus on the cytotoxic effects exerted by several PPs, among which clofibrate, on different types of tumor cells, with particular reference to the mechanisms of cell death and to their relevance to cancer induction and progression.
Topics: Animals; Clofibrate; Cytotoxins; Disease Progression; Humans; Neoplasms; Peroxisome Proliferator-Activated Receptors; Peroxisome Proliferators
PubMed: 20015045
DOI: 10.2174/092986710790192712 -
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 -
Physiological Reviews Jan 1998In the decade that has elapsed since the discovery of the first peroxisomal targeting signal (PTS), considerable information has been obtained regarding the mechanism of... (Review)
Review
In the decade that has elapsed since the discovery of the first peroxisomal targeting signal (PTS), considerable information has been obtained regarding the mechanism of protein import into peroxisomes. The PTSs responsible for the import of matrix and membrane proteins to peroxisomes, the receptors for several of these PTSs, and docking proteins for the PTS1 and PTS2 receptors are known. Many peroxins involved in peroxisomal protein import and biogenesis have been characterized genetically and biochemically. These studies have revealed important new insights regarding the mechanism of protein translocation across the peroxisomal membrane, the conservation of PEX genes through evolution, the role of peroxins in fatal human peroxisomal disorders, and the biogenesis of the organelle. It is clear that peroxisomal protein import and biogenesis have many features unique to this organelle alone. More recent studies on peroxisome degradation, division, and movement highlight newer aspects of the biology of this organelle that promise to be just as exciting and interesting as import and biogenesis.
Topics: Animals; Humans; Membrane Proteins; Microbodies; PHEX Phosphate Regulating Neutral Endopeptidase; Peroxisomal Disorders; Protein Biosynthesis; Protein Conformation; Proteins; Signal Transduction
PubMed: 9457172
DOI: 10.1152/physrev.1998.78.1.171 -
Critical Reviews in Toxicology May 2006The industrial plasticizer di-(2-ethylhexyl)phthalate (DEHP) is used in manufacturing of a wide variety of polyvinyl chloride (PVC)-containing medical and consumer... (Review)
Review
The industrial plasticizer di-(2-ethylhexyl)phthalate (DEHP) is used in manufacturing of a wide variety of polyvinyl chloride (PVC)-containing medical and consumer products. DEHP belongs to a class of chemicals known as peroxisome proliferators (PPs). PPs are a structurally diverse group of compounds that share many (but perhaps not all) biological effects and are characterized as non-genotoxic rodent carcinogens. This review focuses on the effect of DEHP in liver, a primary target organ for the pleiotropic effects of DEHP and other PPs. Specifically, liver parenchymal cells, identified herein as hepatocytes, are a major cell type that are responsive to exposure to PPs, including DEHP; however, other cell types in the liver may also play a role. The PP-induced increase in the number and size of peroxisomes in hepatocytes, so called 'peroxisome proliferation' that results in elevation of fatty acid metabolism, is a hallmark response to these compounds in the liver. A link between peroxisome proliferation and tumor formation has been a predominant, albeit questioned, theory to explain the cause of a hepatocarcinogenic effect of PPs. Other molecular events, such as induction of cell proliferation, decreased apoptosis, oxidative DNA damage, and selective clonal expansion of the initiated cells have been also been proposed to be critically involved in PP-induced carcinogenesis in liver. Considerable differences in the metabolism and molecular changes induced by DEHP in the liver, most predominantly the activation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)alpha, have been identified between species. Both sexes of rats and mice develop adenomas and carcinomas after prolonged feeding with DEHP; however, limited DEHP-specific human data are available, even though exposure to DEHP and other phthalates is common in the general population. This likely constitutes the largest gap in our knowledge on the potential for DEHP to cause liver cancer in humans. Overall, it is believed that the sequence of key events that are relevant to DEHP-induced liver carcinogenesis in rodents involves the following events whereby the combination of the molecular signals and multiple pathways, rather than a single hallmark event (such as induction of PPARalpha and peroxisomal genes, or cell proliferation) contribute to the formation of tumors: (i) rapid metabolism of the parental compound to primary and secondary bioactive metabolites that are readily absorbed and distributed throughout the body; (ii) receptor-independent activation of hepatic macrophages and production of oxidants; (iii) activation of PPARalpha in hepatocytes and sustained increase in expression of peroxisomal and non-peroxisomal metabolism-related genes; (iv) enlargement of many hepatocellular organelles (peroxisomes, mitochondria, etc.); (v) rapid but transient increase in cell proliferation, and a decrease in apoptosis; (vi) sustained hepatomegaly; (vii) chronic low-level oxidative stress and accumulation of DNA damage; (viii) selective clonal expansion of the initiated cells; (ix) appearance of the pre-neoplastic nodules; (x) development of adenomas and carcinomas.
Topics: Animals; Cell Proliferation; Hepatocytes; Humans; Peroxisomes; Phthalic Acids; Plasticizers; Species Specificity
PubMed: 16954067
DOI: 10.1080/10408440600779065 -
FEBS Open Bio Dec 2022When skeletal muscle is damaged, satellite cells (SCs) are activated to proliferate rapidly and fuse with the damaged muscle fibers to form new muscle fibers, thereby...
When skeletal muscle is damaged, satellite cells (SCs) are activated to proliferate rapidly and fuse with the damaged muscle fibers to form new muscle fibers, thereby promoting muscle growth and remodeling and repair of trauma. Exosomes from differentiating human skeletal muscle cells trigger myogenesis of stem cells and provide biochemical cues for skeletal muscle regeneration. Therefore, we hypothesized that, when muscles are injured, myoblast-derived exosomes may regulate muscle repair and regeneration. Here, we investigated the underlying mechanism by applying C2C12-derived exosomes to injured mouse skeletal muscles. The expression levels of skeletal muscle regeneration factors paired box 7 and lipid-promoting factor peroxisome proliferator-activated receptor γ were upregulated, whereas the expression levels of fibrosis factors collagen-1 and α-smooth muscle actin decreased. The expression of proliferating cell nuclear antigen was elevated after applying C2C12-derived exosomes to SCs. Application of C2C12-derived exosomes to fibro-adipogenic progenitors resulted in an increase in peroxisome proliferator-activated receptor γ expression and adipogenesis capacity, whereas α-smooth muscle actin expression and fibrosis capacity decreased. Analysis of the transcriptome and proteome of SCs after treatment with exosomes showed the involvement of multiple biological processes, including proliferation and differentiation of SCs, muscle regeneration, skeletal muscle atrophy, and the inflammatory response after muscle injury. Hence, our data suggest that C2C12-derived exosomes can promote the regeneration of skeletal muscle fibers, accelerate the production of fat from damaged muscles, inhibit the fibrosis of damaged muscles, and accelerate injury repair, which is related to exosome-mediated regulation of the proliferation of SCs, differentiation of fibro-adipogenic progenitors, and modulation of SC mRNA expression and protein formation and decomposition.
Topics: Mice; Humans; Animals; Exosomes; PPAR gamma; Actins; Myoblasts; Muscle, Skeletal; Fibrosis
PubMed: 36325691
DOI: 10.1002/2211-5463.13504 -
International Journal of Molecular... Mar 2023Benign prostatic hyperplasia (BPH) is a common disease in elderly men with an uncertain etiology and mechanistic basis. Metabolic syndrome (MetS) is also a very common...
Benign prostatic hyperplasia (BPH) is a common disease in elderly men with an uncertain etiology and mechanistic basis. Metabolic syndrome (MetS) is also a very common illness and is closely related to BPH. Simvastatin (SV) is one of the widely used statins for MetS. Peroxisome-proliferator-activated receptor gamma (PPARγ), crosstalking with the WNT/β-catenin pathway, plays important roles in MetS. Our current study aimed to examine SV-PPARγ-WNT/β-catenin signaling in the development of BPH. Human prostate tissues and cell lines plus a BPH rat model were utilized. Immunohistochemical, immunofluorescence, hematoxylin and eosin (H&E) and Masson's trichrome staining, construction of a tissue microarray (TMA), ELISA, CCK-8 assay, qRT-PCR, flow cytometry, and Western blotting were also performed. PPARγ was expressed in both prostate stroma and epithelial compartments and downregulated in BPH tissues. Furthermore, SV dose-dependently triggered cell apoptosis and cell cycle arrest at the G0/G1 phase and attenuated tissue fibrosis and the epithelial-mesenchymal transition (EMT) process both in vitro and in vivo. SV also upregulated the PPARγ pathway, whose antagonist could reverse SV produced in the aforementioned biological process. Additionally, crosstalk between PPARγ and WNT/β-catenin signaling was demonstrated. Finally, correlation analysis with our TMA containing 104 BPH specimens showed that PPARγ was negatively related with prostate volume (PV) and free prostate-specific antigen (fPSA) and positively correlated with maximum urinary flow rate (Qmax). WNT-1 and β-catenin were positively related with International Prostate Symptom Score (IPSS) and nocturia, respectively. Our novel data demonstrate that SV could modulate cell proliferation, apoptosis, tissue fibrosis, and the EMT process in the prostate through crosstalk between PPARγ and WNT/β-catenin pathways.
Topics: Male; Humans; Rats; Animals; Aged; Prostatic Hyperplasia; PPAR gamma; beta Catenin; Simvastatin; Peroxisomes; Wnt Signaling Pathway; Cell Proliferation; Fibrosis
PubMed: 36902342
DOI: 10.3390/ijms24054911 -
PloS One 2015We previously found that peroxisomal biogenesis factor 11a (Pex11a) deficiency is associated with a reduction in peroxisome abundance and impaired fatty acid metabolism...
We previously found that peroxisomal biogenesis factor 11a (Pex11a) deficiency is associated with a reduction in peroxisome abundance and impaired fatty acid metabolism in hepatocytes, and results in steatosis. In the present study, we investigated whether butyrate induces Pex11a expression and peroxisome proliferation, and studied its effect on lipid metabolism. C57BL/6 mice fed standard chow or a high-fat diet (HFD) were treated with tributyrin, 4-phelybutyrate acid (4-PBA), or the butyrate-producing probiotics (Clostridium butyricum MIYAIRI 588 [CBM]) plus inulin (dietary fiber), and the body weight, white adipose tissue, serum triglycerides, mRNA expression, and peroxisome abundance were evaluated. Tributyrin or 4-PBA treatment significantly decreased body weight and increased hepatic mRNA expression of peroxisome proliferator-activated receptor-α (PPARα) and Pex11a. In addition, 4-PBA treatment increased peroxisome abundance and the expression of genes involved in peroxisomal fatty acid β-oxidation (acyl-coenzyme A oxidase 1 and hydroxysteroid [17-beta] dehydrogenase 4). CBM and inulin administration reduced adipose tissue mass and serum triglycerides, induced Pex11a, acyl-coenzyme A oxidase 1, and hydroxysteroid (17-beta) dehydrogenase 4 genes, and increased peroxisome abundance in mice fed standard chow or an HFD. In conclusion, elevation of butyrate availability (directly through administration of butyrate or indirectly via administration of butyrate-producing probiotics plus fiber) induces PPARα and Pex11a and the genes involved in peroxisomal fatty acid β-oxidation, increases peroxisome abundance, and improves lipid metabolism. These results may provide a new therapeutic strategy against hyperlipidemia and obesity.
Topics: Animals; Butyrates; Clostridium butyricum; Dietary Supplements; Gene Expression Regulation; Inulin; Male; Membrane Proteins; Mice; PPAR alpha; Peroxisomes; Probiotics
PubMed: 25659146
DOI: 10.1371/journal.pone.0117851 -
Biochimica Et Biophysica Acta Dec 2006The discovery of the colocalization of catalase with H2O2-generating oxidases in peroxisomes was the first indication of their involvement in the metabolism of oxygen... (Review)
Review
The discovery of the colocalization of catalase with H2O2-generating oxidases in peroxisomes was the first indication of their involvement in the metabolism of oxygen metabolites. In past decades it has been revealed that peroxisomes participate not only in the generation of reactive oxygen species (ROS) with grave consequences for cell fate such as malignant degeneration but also in cell rescue from the damaging effects of such radicals. In this review the role of peroxisomes in a variety of physiological and pathological processes involving ROS mainly in animal cells is presented. At the outset the enzymes generating and scavenging H2O2 and other oxygen metabolites are reviewed. The exposure of cultured cells to UV light and different oxidizing agents induces peroxisome proliferation with formation of tubular peroxisomes and apparent upregulation of PEX genes. Significant reduction of peroxisomal volume density and several of their enzymes is observed in inflammatory processes such as infections, ischemia-reperfusion injury and hepatic allograft rejection. The latter response is related to the suppressive effects of TNFalpha on peroxisomal function and on PPARalpha. Their massive proliferation induced by a variety of xenobiotics and the subsequent tumor formation in rodents is evidently due to an imbalance in the formation and scavenging of ROS, and is mediated by PPARalpha. In PEX5-/- mice with the absence of functional peroxisomes severe abnormalities of mitochondria in different organs are observed which resemble closely those in respiratory chain disorders associated with oxidative stress. Interestingly, no evidence of oxidative damage to proteins or lipids, nor of increased peroxide production has been found in that mouse model. In this respect the role of PPARalpha, which is highly activated in those mice, in prevention of oxidative stress deserves further investigation.
Topics: Animals; Catalase; Hydrogen Peroxide; Mice; Mice, Knockout; Mitochondria; Oxidative Stress; PPAR alpha; Peroxisome-Targeting Signal 1 Receptor; Peroxisomes; Reactive Oxygen Species; Receptors, Cytoplasmic and Nuclear
PubMed: 17034877
DOI: 10.1016/j.bbamcr.2006.09.006