Slide 1: Peroxisomes in Dermatology
M.Y.ABDEL_MAWLA,MD Zagazig Faculty of Medicine,Zagzig,EGYPT
Slide 2: Peroxisomes
Peroxisomes : intracellular organelles with important roles defined in many metabolic processes. Peroxisomes:in all mamalian cells except erythrocytes ,including kertatinocytes 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
M.Y.Abdel-Mawla Zagazig,Egypt 2
Slide 3: Peroxisomes
The oxidative stress resulting from H2O2 is known to stimulate phospholipase D, associated with the production of phosphatidic acid and diacylglycerol. 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.
M.Y.Abdel-Mawla Zagazig,Egypt 3
Slide 4: Peroxisomes Functions
Peroxisomes play only a minor role in cellular functions. Peroxisomes play an important role in regulating cellular proliferation and differentiation as well as in the modulation of inflammatory mediators. Peroxisomes have broad effects on the metabolism of lipids, hormones. Peroxisomes also affect cellular membranes and adipocyte formation, as well as insulin sensitivity. Peroxisomes play a role in aging and tumorigenesis through their effects on oxidative stress.
M.Y.Abdel-Mawla Zagazig,Egypt 4
Slide 5: How Peroxisomes to Function?
Peroxisomal proliferator activator receptors (PPARs) and ligands for these receptors modulate different peroxisomal functions.
M.Y.Abdel-Mawla
Zagazig,Egypt
5
Slide 6: PPARs Distribution
PPARs are found mainly in tissues associated with high fatty acid metabolism. Thus are expressed mainly in liver, They are also found in kidney, muscle, heart, fat, B and T lymphocytes , vascular smooth muscle and keratinocytes
M.Y.Abdel-Mawla Zagazig,Egypt 6
Slide 7: Peroxisome Proliferator-Activated Receptors (PPARs)
•Nuclear hormone receptor superfamily •Multiple isoforms (α, β (δ), γ) •Unique tissue distribution
M.Y.Abdel-Mawla Zagazig,Egypt 7
Slide 8: Mechanism of PPAR action
PPAR RXRα Co-repressors Ligand Ligands Co-activators PPAR:RXRα
?
?
?
Modulation of gene transcription Biological effect
M.Y.Abdel-Mawla Zagazig,Egypt 8
Slide 9: Mechanism of PPAR action
M.Y.Abdel-Mawla
Zagazig,Egypt
9
Slide 10:
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 Nterminus 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 M.Y.Abdel-Mawla Zagazig,Egypt 10
Slide 11: ACTIVATION OF PPARs
PPARs are held in inactive complex associated with heat shock proteins (HsP). Following binding with ligand or other activation signals . HsP is replaced with retinoic acid receptor (RXR) forming active transcription factor. The active PPAR/RXR heterodimer binds to PPAR response element AGGTCA X AGGTCA to initiate transcription of relevant genes.
M.Y.Abdel-Mawla
Zagazig,Egypt
11
Slide 12: Biological roles of PPARα
PPARα mediates the induction of multiple enzymes required to mobilize and transport fatty acids from adipose stores to liver for catabolism. Basis for Zagazig,Egypt therapeutic use in humans toM.Y.Abdel-Mawla lipids. lower serum
12
Slide 13: Biological roles of PPARβ/δ
Ligand activation of PPARβ/δ leads to terminal differentiation of keratinocytes as shown by four independent laboratories. Activation of PPARβ/δ in skeletal muscle leads to increased catabolism of fatty acids and improved insulin sensitivity.
M.Y.Abdel-Mawla
Zagazig,Egypt
13
Slide 14: Biological roles of PPARγ
The role of PPARγ in carcinogenesis is also controversial. There is evidence that activation of PPARγ can either potentiate or attenuate cancer, but current consensus favors attenuation.
M.Y.Abdel-Mawla
Zagazig,Egypt
14
Slide 15: Orchestration of Immune Responses
CELLS Lymphocytes Monocytes/Macs Neutrophils Eosinophils Basophils Dendritic cells MOLECULES Complement Lysozyme Inflammatory mediators Chemokines Cytokines
TISSUES Thymus Spleen Lymph nodes Blood
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
M.Y.Abdel-Mawla Zagazig,Egypt 15
Slide 16: Role of PPARα in Immune Function
•Expressed in monocytes/macrophages, increased after treatment with phorbol ester •PPARα ligands induce apoptosis in activated macrophages •PPARα ligands decrease secretion of MMPs in LPS-treated monocytes •PPARα ligands decrease NOS activity in macrophages BUT… •Natural PPARα ligands increase NOS activity in macrophages
M.Y.Abdel-Mawla Zagazig,Egypt 16
Slide 17: Role of PPARα in Immune Function
•Inflammatory response induced by LTB4 is enhanced in PPARαnull mice •PPARα ligands can inhibit inflammatory cytokine production BUT… •PPARα ligands cause increase in serum TNFα after LPS
M.Y.Abdel-Mawla
Zagazig,Egypt
17
Slide 18: Role of PPARα in Immune Function
•Reports suggest that PPARα ligands are anti-inflammatory but there are also some reports suggesting that PPARα ligands are proinflammatory
M.Y.Abdel-Mawla
Zagazig,Egypt
18
Slide 19: M.Y.Abdel-Mawla
Zagazig,Egypt
19
Slide 20: Peroxisomes &Inflammation
PPAR-a activation: transcription factor for peroxisomal metabolism for arachidonicderived proinflammatory eicosanoids. ligands for this activation are the w-3 fatty acids, which may explain their antiinflammatory effects.
M.Y.Abdel-Mawla Zagazig,Egypt
20
Slide 21: Peroxisomes &Inflammation
PPARa repress NFkB transcription, signal transducer and activator of transcriptions (STATs) and AP-1 (Jun/ Fos) transcription and the downstream signaling mechanism. These effects result in the decreased production of inflammatory cytokines, protease production, and some mechanisms for proliferation and apoptotic signaling.
M.Y.Abdel-Mawla Zagazig,Egypt 21
Slide 22: Peroxisomes &Inflammation
Activation of PPARs also modulates endothelial cell adhesion molecules, and endothelial cells express both PPARa and PPAR gamma
M.Y.Abdel-Mawla
Zagazig,Egypt
22
Slide 23: Effects on angiogenesis
Vascular endothelial cell growth factor(VEGF) is a potent endothelial cellspecific mitogen. PPAR agonists have diverse effects on the expression of VEGF . PPAR gamma ligands increase the generation of VEGF , which might be expected to have pro-angiogenic effects.
M.Y.Abdel-Mawla Zagazig,Egypt 23
Slide 24: Peroxisomes and Sterol Metabolism
The levels of 17b-hydroxy forms of sex steroids are regulated by the 17bhydroxysteroid dehydrogenase (17bHSD) family of proteins. The type IV enzyme, found primarily in peroxisomes, possesses a number of unique features
M.Y.Abdel-Mawla
Zagazig,Egypt
24
Slide 25: Peroxisomes and Sterol Metabolism
17b-HSD IV is involved in degradation of branched-chain fatty acids and the side chain of cholesterol. Its expression is stimulated by PPARa ligands
M.Y.Abdel-Mawla
Zagazig,Egypt
25
Slide 26: Peroxisomes in Epidermal Differentiation & Proliferation
A well documented effects of PPARs on gene transcription associated with lipid metabolism & energy homeostasis. Roles in epidermal maturation, repair and angiogenesis are highlighted.
M.Y.Abdel-Mawla Zagazig,Egypt 26
Slide 27: Peroxisomes in Epidermal Differentiation & Proliferation
1. 2. 3.
4. 5.
PPARα has a role in barrier development. Activators of PPARα, such as clofibrate, oleic acid and linoleic acid, accelerate the barrier development. as evidenced by: decreased transepidermal water loss (TEWL); increased epidermal stratification; the appearance of mature lamellae in the extracellular spaces of a multilayered stratum corneum. the induction of b-galactosidase and steroid sulphatase, accelerated the expression of profilaggrin, and its processing to filaggrin, and the expression of M.Y.Abdel-Mawla Zagazig,Egypt loricrin, a
27
Slide 28: Peroxisomes in Epidermal Differentiation & Proliferation
PPARa ligands : to promote epidermal differentiation,to restore epidermal homeostasis in hyperproliferative mouse epidermis and regulate apoptosis. PPARb ⁄ gamma:induced expression of involucrin and transglutaminase( markers of keratinocyte differentiation)
M.Y.Abdel-Mawla Zagazig,Egypt 28
Slide 29: Wound healing
PPARa and PPARb ⁄ gamma:expression is upregulated in the keratinocytes at the wound edge of the damaged skin. PPARa is re-expressed transiently in this area during the early inflammatory phase of the healing. Delays in wound healing parallel the pattern of PPAR expression of the respective PPAR isotypes PPARb upregulation : linked to proinflammatory cytokines, such as interferon, tumour necrosis factor (TNF)-a.
M.Y.Abdel-Mawla Zagazig,Egypt 29
Slide 30: Wound healing
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.
M.Y.Abdel-Mawla Zagazig,Egypt 30
Slide 31: Sebocyte glands
Activation of PPAR gamma &a by their respective specific ligands, stimulates lipid droplet accumulation in sebocytes. 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.
M.Y.Abdel-Mawla Zagazig,Egypt 31
Slide 32: Psoriasis
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.
M.Y.Abdel-Mawla Zagazig,Egypt 32
Slide 33: Psoriasis
PPARs : a critical regulator of cutaneous homeostasis in psoriasis. In view of their prodifferentiating, antiproliferative & immunomodulating effects, PPAR ligands may be interesting compounds for the treatment of epidermal disorders showing inflammation,hyperproliferation& aberrant differentiation, such as psoriasis.
M.Y.Abdel-Mawla Zagazig,Egypt 33
Slide 34: Psoriasis
The expression of both PPARa & gamma is decreased in epidermis , whereas the exact opposite happens with PPAR dela. Treatment by troglitazone, a specific PPAR gamma activator, inhibited the proliferation of both normal and psoriatic human keratinocytes
M.Y.Abdel-Mawla Zagazig,Egypt 34
Slide 35: Psoriasis
There may be an association between psoriasis and the genes encoding PPARa or PPAR gamma
M.Y.Abdel-Mawla
Zagazig,Egypt
35
Slide 36: Effects on angiogenesis
Vascular endothelial cell growth factor(VEGF) is a potent endothelial cellspecific mitogen. PPAR agonists have diverse effects on the expression of VEGF . PPAR gamma ligands increase the generation of VEGF , which might be expected to have pro-angiogenic effects.
M.Y.Abdel-Mawla Zagazig,Egypt 36
Slide 37: Human immunodeficiency virus-1-protease inhibitor associated lipodystrophy HIV-1-protease inhibitor-associated lipodystrophy : the result of impaired cellular retinoic acid binding protein type I (CRABP-1)-mediated 9-cis retinoic stimulation of PPARc:RXR. 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 Reduced SREBP1 expression consequently alters the PPAR gamma activity, which may lead to lipodystrophy and to metabolic alterations.
M.Y.Abdel-Mawla Zagazig,Egypt 37
Slide 38: Peroxisome defects
1. 2. 3. 4. 5.
There are now many inherited disorders known to relate to peroxisome defects, frequently with significant cutaneous manifestations such as ichthyosis Recurrent ulceration, alopecia, follicular atrophoderma And photosensitivity, Thus ,it is suggested that modification of their activity may be of therapeutic benefit in the field of dermatology
M.Y.Abdel-Mawla Zagazig,Egypt 38
Slide 39: Summary
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. The PPAR subfamily consists of three isotypes: PPARα, PPARβ/δ and PPARγ, which have all been identified in keratinocytes.
M.Y.Abdel-Mawla Zagazig,Egypt 39
Slide 40: Summary
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. PPARβ/δ is significantly upregulated upon various conditions that result in keratinocyte proliferation, and during skin wound healing.
M.Y.Abdel-Mawla Zagazig,Egypt 40
Slide 41: Summary
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. 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, 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.
M.Y.Abdel-Mawla
Zagazig,Egypt
41
Slide 42: A Message Home
Peroxisomes are small cellular organelles that were almost ignored for years because they were believed to play only a minor role in cellular functions. Peroxisomes play an important role in regulating cellular proliferation and differentiation as well as in the modulation of inflammatory mediators. Peroxisomes have broad effects on the metabolism of lipids, hormones,. Through their effects on lipid metabolism, peroxisomes also affect cellular membranes and adipocyte formation, as well as insulin sensitivity Peroxisomes play a role in aging and tumorigenesis through their effects on oxidative stress.
M.Y.Abdel-Mawla
Zagazig,Egypt
42
Slide 43: THANK YOU
M.Y.Abdel-Mawla
Zagazig,Egypt
43
