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Biochimica Et Biophysica Acta May 2016Peroxisomes proliferate by growth and division of pre-existing peroxisomes or could arise de novo. Though the de novo pathway of peroxisome biogenesis is a more recent... (Review)
Review
Peroxisomes proliferate by growth and division of pre-existing peroxisomes or could arise de novo. Though the de novo pathway of peroxisome biogenesis is a more recent discovery, several studies have highlighted key mechanistic details of the pathway. The endoplasmic reticulum (ER) is the primary source of lipids and proteins for the newly-formed peroxisomes. More recently, an intricate sorting process functioning at the ER has been proposed, that segregates specific PMPs first to peroxisome-specific ER domains (pER) and then assembles PMPs selectively into distinct pre-peroxisomal vesicles (ppVs) that later fuse to form import-competent peroxisomes. In addition, plausible roles of the three key peroxins Pex3, Pex16 and Pex19, which are also central to the growth and division pathway, have been suggested in the de novo process. In this review, we discuss key developments and highlight the unexplored avenues in de novo peroxisome biogenesis.
Topics: Animals; Endoplasmic Reticulum; Eukaryotic Cells; Fungal Proteins; Gene Expression Regulation; Humans; Membrane Proteins; Organelle Biogenesis; Peroxins; Peroxisomes; Plants; Protein Isoforms; Protein Structure, Tertiary; Protein Transport; Saccharomyces cerevisiae Proteins; Signal Transduction; Yeasts
PubMed: 26381541
DOI: 10.1016/j.bbamcr.2015.09.014 -
Cell Biochemistry and Biophysics 2000Peroxisomes in liver parenchymal cells proliferate in response to structurally diverse nonmutagenic compounds designated as peroxisome proliferators (PP). Sustained... (Review)
Review
Peroxisomes in liver parenchymal cells proliferate in response to structurally diverse nonmutagenic compounds designated as peroxisome proliferators (PP). Sustained induction of peroxisome proliferation and peroxisomal fatty acid beta-oxidation system in rats and mice leads to the development of liver tumors. Two mechanistic issues are important for consideration: elucidation of the upstream events responsible for the tissue and species specific induction of the characteristic pleiotropic responses by PPs; and delineation of the downstream events associated with peroxisome proliferation, and their role in the development of liver tumors in species that are sensitive to the induction of peroxisome proliferation. The induction of peroxisome proliferation is mediated by PP-activated receptor alpha (PPAR alpha), a member of a group of transcription factors that regulate the expression of genes associated with lipid metabolism and adipocyte differentiation. Three isotypes of this family of nuclear receptors, namely PPAR alpha, PPAR gamma, and PPAR delta (also called beta), have been identified as products of separate genes. Although PPAR alpha is responsible for the PP-induced pleiotropic responses, PPAR gamma seems to be involved in adipogenesis and differentiation, but the events associated with PPAR gamma do not directly involve peroxisomes and peroxisome proliferation. PPARs heterodimerize with 9-cis retinoic acid receptor (RXR), and bind to PP response element(s) (PPREs) on the target gene promoter to initiate inducible transcriptional activity. Tissue and species responses to PPs depend on pharmacokinetics, relative abundance of PPAR isotypes, nature of PPRE in the upstream regions of target genes, the extent of competition or cross-talk among nuclear transcription factors for PPAR heterodimerization partner retinoid X receptor and the modulating role of coactivators and corepressors on ligand-dependent transcription of PPARs. Using PPAR as bait in the yeast two-hybrid system, the authors recently cloned mouse steroid receptor coactivator-1 (SRC-1) and PPAR-binding protein (PBP), and identified them as PPAR coactivators. Both SRC-1 and PBP contain LXXLL signature motifs, considered necessary and sufficient for the binding of coactivators to nuclear receptors. A multifaceted approach, which includes the identification of additional coactivators that may be responsible for cell specific transcriptional activation of PPAR-mediated target genes, and generation of genetically modified animals (transgenic and gene disrupted), will be necessary to gain more insight into the upstream and downstream targets responsible for the induction of early and delayed PP-induced pleiotropic responses. In this context, it is important to note that mice deficient in fatty acyl-CoA oxidase, the first and rate-limiting enzyme of the peroxisomal beta-oxidation system, revealed that this enzyme is indispensable for the physiological regulation of PPAR alpha, and the absence of this enzyme leads to sustained transcriptional activation of genes regulated by this receptor.
Topics: Animals; Gene Expression Regulation; Humans; Liver; Peroxisomes; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Transcription Factors
PubMed: 11330046
DOI: 10.1385/cbb:32:1-3:187 -
Nature Medicine Aug 2011Previous studies have proposed roles for hypothalamic reactive oxygen species (ROS) in the modulation of circuit activity of the melanocortin system. Here we show that...
Previous studies have proposed roles for hypothalamic reactive oxygen species (ROS) in the modulation of circuit activity of the melanocortin system. Here we show that suppression of ROS diminishes pro-opiomelanocortin (POMC) cell activation and promotes the activity of neuropeptide Y (NPY)- and agouti-related peptide (AgRP)-co-producing (NPY/AgRP) neurons and feeding, whereas ROS-activates POMC neurons and reduces feeding. The levels of ROS in POMC neurons were positively correlated with those of leptin in lean and ob/ob mice, a relationship that was diminished in diet-induced obese (DIO) mice. High-fat feeding resulted in proliferation of peroxisomes and elevated peroxisome proliferator-activated receptor γ (PPAR-γ) mRNA levels within the hypothalamus. The proliferation of peroxisomes in POMC neurons induced by the PPAR-γ agonist rosiglitazone decreased ROS levels and increased food intake in lean mice on high-fat diet. Conversely, the suppression of peroxisome proliferation by the PPAR antagonist GW9662 increased ROS concentrations and c-fos expression in POMC neurons. Also, it reversed high-fat feeding-triggered elevated NPY/AgRP and low POMC neuronal firing, and resulted in decreased feeding of DIO mice. Finally, central administration of ROS alone increased c-fos and phosphorylated signal transducer and activator of transcription 3 (pStat3) expression in POMC neurons and reduced feeding of DIO mice. These observations unmask a previously unknown hypothalamic cellular process associated with peroxisomes and ROS in the central regulation of energy metabolism in states of leptin resistance.
Topics: Agouti-Related Protein; Anilides; Animals; Cell Line; Eating; Electrophysiology; Energy Metabolism; Green Fluorescent Proteins; Hypothalamus; Leptin; Mice; Mice, Obese; Neurons; Neuropeptide Y; PPAR gamma; Peroxisomes; Polymerase Chain Reaction; Pro-Opiomelanocortin; Reactive Oxygen Species
PubMed: 21873987
DOI: 10.1038/nm.2421 -
Clinical Chemistry and Laboratory... Jun 2001One of the most rapidly developing areas of organelle biology, which has a major involvement in biochemical pharmacology, is the research into the peroxisomal function.... (Review)
Review
One of the most rapidly developing areas of organelle biology, which has a major involvement in biochemical pharmacology, is the research into the peroxisomal function. There is a large group of compounds that are capable of inducing liver enlargement, proliferation of peroxisomal structures, and induction of peroxisomal and extraperoxisomal fatty acid-oxidizing enzymes in rodent liver, called peroxisome proliferators. This list includes hypolipidemic drugs, analgesics, uricosuric drugs, environmental pollutants, phthalates, etc. Some peroxisome proliferators have also been shown to increase the incidence of liver tumors. This review describes the characteristics of peroxisome proliferation in rodent liver and gives examples of different classes of chemicals that produce this effect. Mechanisms of initiation of peroxisome proliferation in rodent hepatocytes, including peroxisome proliferator-activated receptors, are also described. Rodent peroxisome proliferators are not considered to be genotoxic agents. Proposed mechanisms of liver tumor formation include induction of sustained oxidative stress, enhanced cell replication, promotion of spontaneous preneoplastic lesions, and inhibition of apoptosis. In addition, the absence of effects of peroxisome proliferators on peroxisome proliferator-associated parameters supports the hypothesis that human liver cells are refractory to peroxisome proliferator-induced hepatic carcinogenesis.
Topics: Animals; Carcinogens; Cell Division; Cocarcinogenesis; Humans; Liver; Liver Neoplasms, Experimental; Mice; Models, Biological; Oxidative Stress; Peroxisome Proliferators; Peroxisomes; Rats; Species Specificity
PubMed: 11506454
DOI: 10.1515/CCLM.2001.076 -
TheScientificWorldJournal May 2002Exposure to agonists of peroxisome proliferator-activated receptor alpha (PPARalpha) causes liver cancer in rodents, with aged animals being more susceptible than their... (Review)
Review
Enhanced hepatocarcinogenicity due to agonists of peroxisome proliferator-activated receptors in senescent rats: role of peroxisome proliferation, cell proliferation, and apoptosis.
Exposure to agonists of peroxisome proliferator-activated receptor alpha (PPARalpha) causes liver cancer in rodents, with aged animals being more susceptible than their younger counterparts to this effect. Treatment with these chemicals produced a five- to sevenfold higher yield of grossly visible hepatic tumors in old rats compared to young animals. The enhanced susceptibility of the aged livers to the carcinogenic effect of PPAR agonists could not be explained by differences in levels of peroxisomal and/or cell proliferation between young and old animals, as neither of these responses was exaggerated with aging. Reported studies have shown that activating PPARalpha results in the suppression of hepatic apoptosis. This effect is expected to diminish the ability of the liver to purge itself of pre-existing neoplastic cells, allowing them to progress to tumors. New findings from our laboratories show that the aged liver is exceedingly sensitive to the antiapoptotic effect of PPAR agonists. In addition, aged livers showed remarkably higher levels of the antiapoptotic protein Bcl-2 than livers of young, adult, and middle-aged animals. Interestingly, the PPARalpha agonist Wy-14,643 significantly diminished elements of the proapoptotic machinery (e.g., Bax, caspases, and fas) in the aged liver, while remarkably increasing elements of this machinery in younger animals. Taken together, while activation of PPARs appears to inhibit apoptosis in livers of senescent animals, activating these receptors seems to stimulate the apoptotic machinery in young animals. This paradoxical effect may be responsible for the exaggerated sensitivity of the aged liver to the carcinogenic effect of agents that activate PPARs.
Topics: Aging; Animals; Apoptosis; Cell Division; Hepatocytes; Humans; Liver Neoplasms; Models, Molecular; Peroxisome Proliferators; Peroxisomes; Rats; Receptors, Cytoplasmic and Nuclear; Transcription Factors
PubMed: 12805935
DOI: 10.1100/tsw.2002.352 -
Plant Signaling & Behavior Sep 2008Peroxisomes are subcellular organelles with multiple functions mediated by their plasticity and dynamic behavior in plants. Changes in their shape, size, number and...
Peroxisomes are subcellular organelles with multiple functions mediated by their plasticity and dynamic behavior in plants. Changes in their shape, size, number and enzyme content occur in response to developmental and metabolic cues as well as environmental conditions. The number of peroxisomes per cell is thus mainly determined by its capacity to proliferate. In mammals, peroxisome proliferators such as the hypolipidemic drug clofibrate are perceived by the Peroxisome Proliferator-Activated Receptors (PPARs) nuclear receptors. Therein, activated transcription of the peroxisome biogenesis PEX11 genes and the recruitment of dynamin-related proteins lead to peroxisome proliferation. We recently reported that Arabidopsis thaliana, despite of lacking a PPAR homolog protein, activated the proliferation of peroxisomes in response to clofibrate. Concomitantly, clofibrate activated the expression of wound-responsive genes through the jasmonic acid signaling master regulator COI1 F-box protein. Besides, wounding activated the expression of the peroxisome biogenesis-related PEX1 and PEX14 genes, but not of PEX11 or DRP3A, which analogously to mammals, code for the main regulators of peroxisome proliferation in Arabidopsis. Thus, wounding did not activate peroxisome proliferation. Noteworthy, jasmonic acid-treated plants contained fewer but larger peroxisomes. Despite of the cross-talk between clofibrate- and wound-induced signaling, the proliferation of peroxisomes and the wound-activated defense remained uncoupled.
PubMed: 19704821
DOI: 10.4161/psb.3.9.5780 -
Journal of Cellular and Molecular... 2003Peroxisomes are metabolic organelles with enzymatic content that are found in virtually all cells and are involved in beta-oxidation of fatty acids, hydrogen... (Review)
Review
Peroxisomes are metabolic organelles with enzymatic content that are found in virtually all cells and are involved in beta-oxidation of fatty acids, hydrogen peroxide-based respiration and defence against oxidative stress. The steps of their biogenesis involves "peroxins", proteins encoded by PEX genes. Peroxins are involved in three key stages of peroxisome development: (1). import of peroxisomal membrane proteins; (2). import of peroxisomal matrix proteins and (3). peroxisome proliferation. Of these three areas, peroxisomal matrix-protein import is by far the best understood and accounts for most of the available published data on peroxisome biogenesis. Defects in peroxisome biogenesis result in peroxisome biogenesis disorders (PBDs), which although rare, have no known cure to-date. This review explores current understanding of each key area in peroxisome biogenesis, paying particular attention to the role of protein import.
Topics: Animals; Biological Transport, Active; Humans; Membrane Proteins; Peroxisomes; Plants; Proteins; Saccharomyces cerevisiae
PubMed: 14754507
DOI: 10.1111/j.1582-4934.2003.tb00241.x -
Frontiers in Physiology 2014We have evaluated the current knowledge on peroxisome proliferation in yeast. In wild-type cells, peroxisomes multiply predominantly by fission at conditions that... (Review)
Review
We have evaluated the current knowledge on peroxisome proliferation in yeast. In wild-type cells, peroxisomes multiply predominantly by fission at conditions that require peroxisome function(s) for growth. In cells that lack peroxisomes, for instance in pex3 and pex19 mutants or in mutants that display inheritance defects, peroxisomes may form de novo. We propose a novel machinery for the de novo formation of peroxisomes in pex3 cells, in which new peroxisomes do not arise from the endoplasmic reticulum. This machinery is based on the recent observation that membrane vesicles are present in pex3 cells that display peroxisomal characteristics in that they contain specific peroxisomal membrane and matrix proteins. These structures are the source for newly formed peroxisomes upon reintroduction of Pex3. Furthermore, we critically evaluate the principles of sorting of other peroxisomal membrane proteins to their target organelle and the function of the endoplasmic reticulum therein.
PubMed: 24688473
DOI: 10.3389/fphys.2014.00110 -
ELife Jan 2021Curcumin is a polyphenol compound that exhibits multiple physiological activities. To elucidate the mechanisms by which curcumin affects systemic amyloidosis, we...
Curcumin is a polyphenol compound that exhibits multiple physiological activities. To elucidate the mechanisms by which curcumin affects systemic amyloidosis, we investigated amyloid deposition and molecular changes in a mouse model of amyloid apolipoprotein A-II (AApoAII) amyloidosis, in which mice were fed a curcumin-supplemented diet. Curcumin supplementation for 12 weeks significantly increased AApoAII amyloid deposition relative to controls, especially in the liver and spleen. Liver weights and plasma ApoA-II and high-density lipoprotein concentrations were significantly elevated in curcumin-supplemented groups. RNA-sequence analysis revealed that curcumin intake affected hepatic lipid metabolism via the peroxisome proliferator-activated receptor (PPAR) pathway, especially PPARα activation, resulting in increased mRNA expression. The increase in liver weights was due to activation of PPARα and peroxisome proliferation. Taken together, these results demonstrate that curcumin is a PPARα activator and may affect expression levels of proteins involved in amyloid deposition to influence amyloidosis and metabolism in a complex manner.
Topics: Amyloidosis; Animals; Apolipoprotein A-II; Curcumin; Female; Mice; PPAR alpha; Peroxisomes; Signal Transduction
PubMed: 33496266
DOI: 10.7554/eLife.63538 -
International Journal of Molecular... Sep 2021Although peroxisomes play an essential role in viral pathogenesis, and viruses are known to change peroxisome morphology, the role of genotype in the peroxisomal...
Although peroxisomes play an essential role in viral pathogenesis, and viruses are known to change peroxisome morphology, the role of genotype in the peroxisomal response to viruses remains poorly understood. Here, we analyzed the impact of wheat streak mosaic virus (WSMV) on the peroxisome proliferation in the context of pathogen response, redox homeostasis, and yield in two wheat cultivars, Patras and Pamir, in the field trials. We observed greater virus content and yield losses in Pamir than in Patras. Leaf chlorophyll and protein content measured at the beginning of flowering were also more sensitive to WSMV infection in Pamir. Patras responded to the WSMV infection by transcriptional up-regulation of the peroxisome fission genes (), (), and (), greater peroxisome abundance, and activation of pathogenesis-related proteins chitinase, and β-1,3-glucanase. Oppositely, in Pamir, WMSV infection suppressed transcription of peroxisome biogenesis genes and activity of chitinase and β-1,3-glucanase, and did not affect peroxisome abundance. Activity of ROS scavenging enzymes was higher in Patras than in Pamir. Thus, the impact of WMSV on peroxisome proliferation is genotype-specific and peroxisome abundance can be used as a proxy for the magnitude of plant immune response.
Topics: Chitinases; Chlorophyll; Disease Resistance; Glucan 1,3-beta-Glucosidase; Oxidation-Reduction; Peroxidases; Peroxisomes; Phenotype; Plant Diseases; Plant Leaves; Potyviridae; Reactive Oxygen Species; Triticum
PubMed: 34638559
DOI: 10.3390/ijms221910218