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Peroxisomes in dermatology


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The peroxisomes functions and relation to skin disorders.their role in development of skin diseases

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  • salam Alikum prof. dr. Mohamed ,
    My essey is in peroxisomes & i found your site while searching the web, can i ask you for your help ?
    i've already finished writing the introduction & chapter one ,i'm trying to gather informations in dermatological diseases due to peroxisomal disorders.
    thank you so much
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Peroxisomes in dermatology

  1. 1. Peroxisomes in Dermatology <ul><li>M.Y.ABDEL_MAWLA,MD </li></ul><ul><li>Zagazig Faculty of Medicine,Zagzig,EGYPT </li></ul>
  2. 2. The Peroxisome <ul><li>Single membrane </li></ul><ul><li>Roughly spherical </li></ul><ul><ul><li>0.2 - 1.7  m </li></ul></ul><ul><li>Composition varies </li></ul>
  3. 3. Protein Import <ul><li>C-terminal signal sequence: SKL </li></ul><ul><li>N-terminal signal sequence: RLX 5 HL </li></ul><ul><li>Proteins involved in import: peroxins </li></ul><ul><li>Import driven by ATP hydrolysis </li></ul><ul><li>Don’t have to be unfolded for import </li></ul>
  4. 4. Peroxisomes <ul><li>Peroxisomes : intracellular organelles with important roles defined in many metabolic processes. </li></ul><ul><li>Peroxisomes:in all mamalian cells,including kertatinocytes </li></ul><ul><li>They derive their name from their ability to produce H2O2 through a group of oxidizing enzymes which use molecular oxygen to transform their substrates, releasing H2O2 and OH </li></ul>
  5. 5. Peroxisomes <ul><li>The oxidative stress resulting from H2O2 is known to stimulate phospholipase D, associated with the production of phosphatidic acid and diacylglycerol. </li></ul><ul><li>These in turn affect adenylyl cyclase and protein kinase C, respectively, which can modulate a wide array of target proteins including plasma membrane receptors, contractile proteins and regulatory enzymes. </li></ul>
  6. 6. Peroxisomes Biogenesis <ul><li>The development of peroxisomes involves a series of events including the recruitment of (phospho)lipids, synthesis, sorting and assembly/activation of matrix &membrane proteins. </li></ul><ul><li>The peroxisomal membrane mainly consists of phosphatidylcholine &phosphatidylethanolamine and largely resembles that of the endoplasmic reticulum (ER) </li></ul>
  7. 7. Two Models for Peroxisome Biogenesis
  8. 8. Peroxisomes Biogenesis <ul><li>Membrane proteins are synthesized on free polysomes in the cytosol. </li></ul><ul><li>The model discriminates between membrane proteins essential for the biogenesis of organelles (PMBs) and those involved in the organellar function (PMFs, e.g. transporters). </li></ul><ul><li>PMBs (e.g. Pex2p, Pex3p, Pex15p and Pex16p) may initially be transported to the ER and, eventually vesicle-mediated, be sorted to the growing peroxisome; </li></ul><ul><li>PMFs may be transported directly to the organelle </li></ul>
  9. 9. Peroxisomes Functions <ul><li>Peroxisomes play only a minor role in cellular functions. </li></ul><ul><li>Peroxisomes play an important role in regulating cellular proliferation and differentiation as well as in the modulation of inflammatory mediators. </li></ul><ul><li>Peroxisomes have broad effects on the metabolism of lipids, hormones. </li></ul><ul><li>Peroxisomes also affect cellular membranes and adipocyte formation, as well as insulin sensitivity. </li></ul><ul><li>Peroxisomes play a role in aging and tumorigenesis through their effects on oxidative stress. </li></ul>
  10. 11. Peroxisomal Enzymes
  11. 12. Key peroxisomal enzymes
  12. 13. How Peroxisomes to Function? <ul><li>Peroxisomes, contribute to key metabolic pathways of the cell function. </li></ul><ul><li>These organelles are able to proliferate abundantly upon exposure to so-called peroxisome proliferators. </li></ul><ul><li>Peroxisome-located enzymes are also regulated by many molecules including nutrients (fatty acids, steroids), hormones (T3, retinoids), PPARs and other nuclear signaling factors. </li></ul>
  13. 14. How Peroxisomes to Function? <ul><li>Peroxisomal proliferator activator receptors ( PPARs ) and ligands for these receptors modulate different peroxisomal functions. </li></ul>
  14. 15. PPARs Distribution <ul><li>PPARs are found mainly in tissues associated with high fatty acid metabolism. </li></ul><ul><li>Thus are expressed mainly in liver, </li></ul><ul><li>They are also found in kidney, muscle, heart, fat, B and T lymphocytes , vascular smooth muscle and keratinocytes </li></ul>
  15. 16. Peroxisome Proliferator-Activated Receptors ( PPARs ) <ul><li>Nuclear hormone receptor superfamily </li></ul><ul><li>Multiple isoforms (  ) </li></ul><ul><li>Unique tissue distribution </li></ul>
  16. 17. PPAR:RXR  Co-repressors Co-activators Modulation of gene transcription ? ? ? Biological effect Mechanism of PPAR action RXR  Ligands PPAR Ligand
  17. 18. Mechanism of PPAR action
  18. 19. <ul><li>Peroxisome proliferator-activated receptors ( PPARs) function as heterodimers with retinoid X receptors (RXRs) and are activated by specific ligands; they then modulate DNA transcription by binding to defined nucleotide sequences (peroxisome proliferator response element, PPRE) in the promoter region of target genes. Several cofactors (coactivators or corepressors) mediate the ability of nuclear receptors to stimulate or repress the transcription process. (b) The N-terminus A/B domain contains a ligand-independent transcriptional activation domain (AF-1), which can be regulated by mitogen-activated protein kinase (MAPK) phosphorylation in α and γ isotypes. The C domain contains two zinc-finger-like motifs that specifically bind the PPRE in the regulatory region of PPAR-responsive genes. The D domain or hinge region allows conformational changes in the molecule. The E/F domain consists of the ligand-binding domain and the ligand-dependent transcriptional activation domain (AF-2). The ligand-binding pocket appears to be quite large in comparison with other nuclear receptors, allowing the PPARs to interact with a broad range of natural and synthetic ligands </li></ul>
  19. 20. ACTIVATION OF PPARs <ul><li>PPARs are held in inactive complex associated with heat shock proteins (HsP). Following binding with ligand or other activation signals . </li></ul><ul><li>HsP is replaced with retinoic acid receptor (RXR) forming active transcription factor. </li></ul><ul><li>The active PPAR/RXR heterodimer binds to PPAR response element AGGTCA X AGGTCA to initiate transcription of relevant genes. </li></ul>
  20. 21. Biological roles of PPAR  PPAR  mediates the induction of multiple enzymes required to mobilize and transport fatty acids from adipose stores to liver for catabolism. Basis for therapeutic use in humans to lower serum lipids.
  21. 22. Biological roles of PPAR  /  Ligand activation of PPAR  /  leads to terminal differentiation of keratinocytes as shown by four independent laboratories. Activation of PPAR  /  in skeletal muscle leads to increased catabolism of fatty acids and improved insulin sensitivity.
  22. 23. Biological roles of PPAR  The role of PPAR  in carcinogenesis is also controversial. There is evidence that activation of PPAR  can either potentiate or attenuate cancer, but current consensus favors attenuation.
  23. 24. Orchestration of Immune Responses TISSUES Thymus Spleen Lymph nodes Blood CELLS Lymphocytes Monocytes/Macs Neutrophils Eosinophils Basophils Dendritic cells MOLECULES Complement Lysozyme Inflammatory mediators Chemokines Cytokines Innate immunity Adaptive Immunity PPARs are found in a number of immune cell types and there is evidence that they could modulate a number of different immune responses
  24. 25. Role of PPAR  in Immune Function <ul><li>Expressed in monocytes/macrophages, increased after treatment with phorbol ester </li></ul><ul><li>PPAR  ligands induce apoptosis in activated macrophages </li></ul><ul><li>PPAR  ligands decrease secretion of MMPs in LPS-treated monocytes </li></ul><ul><li>PPAR  ligands decrease NOS activity in macrophages </li></ul><ul><li>BUT… </li></ul><ul><li>Natural PPAR  ligands increase NOS activity in macrophages </li></ul>
  25. 26. Role of PPAR  in Immune Function <ul><li>Inflammatory response induced by LTB4 is enhanced in PPAR  -null mice </li></ul><ul><li>PPAR  ligands can inhibit inflammatory cytokine production </li></ul><ul><li>BUT… </li></ul><ul><li>PPAR  ligands cause increase in serum TNF  after LPS </li></ul>
  26. 27. Role of PPAR  in Immune Function <ul><li>Reports suggest that PPAR  ligands are anti-inflammatory but there are also some reports suggesting that PPAR  ligands are pro-inflammatory </li></ul>
  27. 29. Peroxisomes &Inflammation <ul><li>PPAR-a activation: transcription factor for peroxisomal metabolism for arachidonic-derived proinflammatory eicosanoids. </li></ul><ul><li>ligands for this activation are the w-3 fatty acids, which may explain their antiinflammatory effects. </li></ul>
  28. 30. Peroxisomes &Inflammation <ul><li>PPARa repress NFkB transcription, signal transducer and activator of transcriptions (STATs) and AP-1 (Jun/ Fos) transcription and the downstream signaling mechanism. </li></ul><ul><li>These effects result in the decreased production of inflammatory cytokines, protease production, and some mechanisms for proliferation and apoptotic signaling. </li></ul>
  29. 31. Peroxisomes &Inflammation <ul><li>Activation of PPARs also modulates endothelial cell adhesion molecules, and endothelial cells express both PPARa and PPAR gamma </li></ul>
  30. 32. Peroxisomes &INFLAMMATION <ul><li>The peroxisome proliferator-activated receptors (PPARs) α, β/δ, and γ are ligand-activated transcription factors belonging to the nuclear receptor superfamily. </li></ul><ul><li>In addition to their regulatory role on lipid and glucose metabolism, they exert anti-inflammatory properties. </li></ul><ul><li>In skin both PPAR-α and PPAR-β/δ regulate keratinocyte proliferation/differentiation and contribute to wound healing. </li></ul><ul><li>The 3 PPAR isoforms are expressed by several cell types recruited into the dermis during inflammation. </li></ul>
  31. 33. Effects on angiogenesis <ul><li>Vascular endothelial cell growth factor( VEGF ) is a potent endothelial cell-specific mitogen. </li></ul><ul><li>PPAR agonists have diverse effects on the expression of VEGF . </li></ul><ul><li>PPAR gamma ligands increase the generation of VEGF , which might be expected to have pro-angiogenic effects. </li></ul>
  32. 34. Peroxisomes and Sterol Metabolism <ul><li>The levels of 17b-hydroxy forms of sex steroids are regulated by the 17b-hydroxysteroid dehydrogenase (17b- </li></ul><ul><li>HSD) family of proteins. </li></ul><ul><li>The type IV enzyme, found primarily in peroxisomes, possesses a number of unique features </li></ul>
  33. 35. Peroxisomes and Sterol Metabolism <ul><li>17b-HSD IV is involved in degradation of branched-chain fatty acids and the side chain of cholesterol. </li></ul><ul><li>Its expression is stimulated by PPARa ligands </li></ul>
  34. 36. Peroxisomes in Epidermal Differentiation & Proliferation <ul><li>A well documented effects of PPARs on gene transcription associated with lipid metabolism & energy homeostasis. </li></ul><ul><li>Roles in epidermal maturation, repair and angiogenesis are highlighted. </li></ul>
  35. 37. Peroxisomes in Epidermal Differentiation & Proliferation <ul><li>PPARα has a role in barrier development. </li></ul><ul><li>Activators of PPARα, such as clofibrate, oleic acid and linoleic acid, accelerate the barrier development. as evidenced by : </li></ul><ul><li>decreased transepidermal water loss (TEWL); </li></ul><ul><li>increased epidermal stratification; </li></ul><ul><li>the appearance of mature lamellae in the extracellular spaces of a multilayered stratum corneum. </li></ul><ul><li>the induction of b-galactosidase and steroid sulphatase, </li></ul><ul><li>accelerated the expression of profilaggrin, and its processing to filaggrin, and the expression of loricrin, a </li></ul>
  36. 38. Peroxisomes & Atopic Dermatitis <ul><li>Changes in immunoglobulin-associated transcription in atopic dermatitis may favour </li></ul><ul><li>IgE over secretory immunoglobulin (multimeric IgM and IgA) expression in AD skin. </li></ul><ul><li>Decreased PPAR activity appears common </li></ul><ul><li>to both AD and psoriasis, and reduced cutaneous IFNa2 transcription also appears characteristic of AD </li></ul>
  37. 39. Peroxisomes in Epidermal Differentiation & Proliferation <ul><li>PPARa ligands : to promote epidermal differentiation,to restore epidermal homeostasis in hyperproliferative </li></ul><ul><li>mouse epidermis and regulate apoptosis. </li></ul><ul><li>PPARb ⁄ gamma:induced expression of involucrin and transglutaminase( markers of keratinocyte differentiation) </li></ul>
  38. 40. Wound healing <ul><li>PPARa and PPARb ⁄ gamma:expression is upregulated in the keratinocytes at the wound edge of the damaged skin. </li></ul><ul><li>PPARa is re-expressed transiently in this area during the early inflammatory phase of the healing. </li></ul><ul><li>Delays in wound healing parallel the pattern of PPAR expression of the respective PPAR isotypes </li></ul><ul><li>PPARb upregulation : linked to </li></ul><ul><li>proinflammatory cytokines, such as </li></ul><ul><li>interferon, tumour necrosis factor (TNF)-a. </li></ul>
  39. 41. Wound healing <ul><li>PPARb : a key mediator ofepidermal effects in wound healing by converting the extracellular inflammatory signal into an organized pattern of gene expression leading to survival, migration and differentiation of keratinocytes. </li></ul>
  40. 42. Sebocyte glands <ul><li>Activation of PPAR gamma &a by their respective specific ligands, stimulates lipid </li></ul><ul><li>droplet accumulation in sebocytes. </li></ul><ul><li>Because increased sebum production is an important element in the pathogenesis of acne vulgaris, development PPAR antagonists interfering selectively with sebum formation may have implications for the treatment of acne. </li></ul>
  41. 43. Psoriasis <ul><li>The hallmarks of psoriasis are abnormal differentiation & hyperproliferation of keratinocytes with inflammatory cell infiltration. These cellular changes are likely to find their explanation in activated T lymphocytes infiltrating the skin. </li></ul>
  42. 44. Psoriasis <ul><li>PPARs : a critical regulator of cutaneous homeostasis in psoriasis. </li></ul><ul><li>In view of their prodifferentiating, antiproliferative & immunomodulating effects, PPAR ligands may be interesting compounds for the treatment of epidermal disorders showing inflammation,hyperproliferation& </li></ul><ul><li>aberrant differentiation, such as psoriasis. </li></ul>
  43. 45. Psoriasis <ul><li>The expression of both PPARa & gamma is decreased in epidermis , whereas the exact opposite happens with PPAR dela . </li></ul><ul><li>Treatment by troglitazone , a specific PPAR gamma activator, inhibited the proliferation of both normal and psoriatic human keratinocytes </li></ul>
  44. 46. Psoriasis <ul><li>There may be an association between </li></ul><ul><li>psoriasis and the genes encoding PPARa or PPAR gamma </li></ul>
  45. 47. Effects on angiogenesis <ul><li>Vascular endothelial cell growth factor( VEGF ) is a potent endothelial cell-specific mitogen. </li></ul><ul><li>PPAR agonists have diverse effects on the expression of VEGF . </li></ul><ul><li>PPAR gamma ligands increase the generation of VEGF , which might be expected to have pro-angiogenic effects. </li></ul>
  46. 48. Human immunodeficiency virus-1-protease inhibitor associated lipodystrophy <ul><li>HIV-1-protease inhibitor-associated lipodystrophy : the result of impaired cellular retinoic acid binding </li></ul><ul><li>protein type I (CRABP-1)-mediated 9-cis retinoic stimulation of PPARc:RXR. </li></ul><ul><li>Altered differentiation status of peripheral adipocytes in HIV-1-infected patients with protease inhibitor lipodystrophy is associated with greatly reduced sterol-regulatory element-binding protein 1c ( SREBP1c) mRNA expression </li></ul><ul><li>Reduced SREBP1 expression consequently alters the PPAR gamma activity, which may lead to lipodystrophy and to metabolic alterations. </li></ul>
  47. 49. Peroxisome defects <ul><li>There are now many inherited disorders known to relate to peroxisome defects, frequently with significant cutaneous manifestations such as </li></ul><ul><li>ichthyosis </li></ul><ul><li>Recurrent ulceration, </li></ul><ul><li>alopecia, </li></ul><ul><li>follicular atrophoderma </li></ul><ul><li>And photosensitivity, </li></ul><ul><li>Thus ,it is suggested that modification of their </li></ul><ul><li>activity may be of therapeutic benefit in the field of dermatology </li></ul>
  48. 53. Summary <ul><li>   Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate the expression of target genes involved in many cellular functions including cell proliferation, differentiation and immune/inflammation response. </li></ul><ul><li>The PPAR subfamily consists of three isotypes: PPARα, PPARβ/δ and PPARγ, which have all been identified in keratinocytes. </li></ul><ul><li>  </li></ul>
  49. 54. Summary <ul><li>PPARβ/δ is the predominant subtype in human keratinocytes, whereas PPARα and PPARγ are expressed at much lower levels and increase significantly upon keratinocyte differentiation. </li></ul><ul><li>PPARβ/δ is significantly upregulated upon various conditions that result in keratinocyte proliferation, and during skin wound healing. </li></ul>
  50. 55. Summary <ul><li>PPARs appear to play an important role in skin barrier permeability, inhibiting epidermal cell growth, promoting epidermal terminal differentiation and regulating skin inflammatory response by diverse mechanisms. </li></ul><ul><li>These proprieties are pointing in the direction of PPARs being key regulators of skin conditions characterized by hyperproliferation, inflammatory infiltrates and aberrant differentiation such as psoriasis, </li></ul><ul><li>They may also have clinical implications in other inflammatory skin disease (e.g. atopic dermatitis), proliferative skin disease, wound healing, acne and protease inhibitor associated lipodystrophia. </li></ul>
  51. 56. A Message Home <ul><li>Peroxisomes are small cellular organelles that were almost ignored for years because they were believed to play only a minor role in cellular functions. </li></ul><ul><li>Peroxisomes play an important role in regulating cellular proliferation and differentiation as well as in the modulation of inflammatory mediators. </li></ul><ul><li>Peroxisomes have broad effects on the metabolism of lipids, hormones,. </li></ul><ul><li>Through their effects on lipid metabolism, peroxisomes also affect cellular membranes and adipocyte formation, as well as insulin sensitivity </li></ul><ul><li>Peroxisomes play a role in aging and tumorigenesis through their effects on oxidative stress. </li></ul>
  52. 57. THANK YOU