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Title: Peroxisomes in Dermatology.ppt


1
Peroxisomes Peroxisome Proliferator-Activator
Receptors in Dermatology
  • M.Y.ABDEL_MAWLA,MD
  • Zagazig Faculty of Medicine,Zagzig,EGYPT

2
Peroxisomes in Cells
  • The trouble with simple things is that one must
  • understand them very well !!!

3
The Peroxisome
  • Single membrane
  • Roughly spherical
  • 0.2 - 1.7?m
  • Composition varies

4
Peroxisomes
  • Peroxisomes intracellular organelles with
    important roles defined in many metabolic
    processes.
  • Peroxisomesin all mamalian cells,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

5
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.

6
Peroxisomes
  • Peroxisomes are similar physically to lysosomes,
    but they are different in two important ways
  • First, they are believed to be formed by
    self-replication (or perhaps by budding off from
    the smooth endoplasmic reticulum) rather than
    from the Golgi apparatus.
  • Second, they contain oxidases rather than
    hydrolases.

7
Peroxisomes Biogenesis
  • The development of peroxisomes involves a series
    of events including the recruitment of
    (phospho)lipids, synthesis, sorting and
    assembly/activation of matrix membrane proteins.
  • The peroxisomal membrane mainly consists of
    phosphatidylcholine phosphatidylethanolamine
    and largely resembles that of the endoplasmic
    reticulum (ER)

8
Peroxisome Biogenesis
9
Peroxisomes Biogenesis
  • Membrane proteins are synthesized on free
    polysomes in the cytosol.
  • The model discriminates between membrane proteins
    essential for the biogenesis of organelles (PMBs)
    and those involved in the organellar function
    (PMFs, e.g. transporters).
  • 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
  • PMFs may be transported directly to the organelle

10
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.

11
Peroxisomes Functions
  • Peroxisomes may be either catabolic or anabolic.
  • Some functions are exclusively peroxisomal
  • Others shared with other cellular compartments
    (microsomes endoplasmic reticulum, and
    mitochondria).

12
Peroxisomes Functions in Cell signaling
  • N nucleus, MIT mitochondria, MIC microsomes,
    Per peroxisome, PKO phosphatidyl choline,
  • PC phosphosphatidyl choline, AA arachidonic
    acid, OX peroxisomal oxidases,
  • LCFA long-chain fatty acids, MCFA
    medium-chain fatty acids, DG diacylglycerol, PA
  • phosphatidic acid, CAT catalase, OFR
    oxygen free radicals.
  • Peroxisome functions involved n cell signaling
    would potentiate differentiation, while reactive
    oxygen species would potentiate tumorigenesis and
    aging and catalase and other peroxisomal
    scavengers would moderate the effects of reactive
    oxygen species

13
Peroxisomes Free Radicles
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15
Peroxisomal Enzymes
16
Key peroxisomal enzymes
17
How Peroxisomes to Function?
  • Peroxisomes, contribute to key metabolic pathways
    of the cell function.
  • These organelles are able to proliferate
    abundantly upon exposure to so-called peroxisome
    proliferators.
  • Peroxisome proliferators may activate PPARs by
    binding directly to the receptors,and the
    activated PPARs may regulate the expression of
    genes involved in lipid metabolism and peroxisome
    proliferation
  • Peroxisome-located enzymes are also regulated by
    many molecules including nutrients (fatty acids,
    steroids), hormones (T3, retinoids), PPARs and
    other nuclear signaling factors.

18
How Peroxisomes to Function?
  • Peroxisomal proliferator activator receptors
    (PPARs) and ligands for these receptors modulate
    different peroxisomal functions.

19
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

20
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21
Peroxisome Proliferator-Activator Receptors
(PPARs)
  • Nuclear hormone receptor superfamily
  • Multiple isoforms (?, ? (d), ?)
  • Unique tissue distribution

22
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23
Mechanism of PPAR action
?
Co-repressors Co-activators
PPARRXR?
?
?
Modulation of gene transcription
Biological effect
24
Mechanism of PPAR action
25
PPARs FUNCTIONS
  • PPARs play a significant role in many in skin
    homeostasis.
  • On binding of ligand, PPARs undergo a
    conformational change enabling them to form a
    heterodimer with the 9-cis retinoic acid receptor
    (RXR).
  • PPAR/RXR complex forms a transcription factor
    able to bind to DNA at PPREs, which are DNA
    sequences specifically capable of recognition
    and binding by the DNA-binding component of this
    transcription factor.

26
PPAR FUNCTIONS
  • A large number of PPAR target genes have been
    identified with wide-ranging effects on cell
    proliferation differentiation, inflammatory
    responses and angiogenesis, as well as lipid and
    glucose metabolism.

27
  • 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 a and ? 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

28
ACTIVATION OF PPARs
  • Most nuclear hormone receptors exist in an
    inactive form complexed with heats hock proteins
  • PPAR activation and regulation may occur either
    following interaction with specific ligands or by
    kinase-mediated phosphorylation, following a
    variety of extracellular signals.
  • Following binding of ligand, the PPAR undergoes a
    conformational change and becomes able to
    interact through the E/F domain with RXR to form
    heterodimers.
  • These dimers will then interact with the cognate
    recognition motif (PPREs) in the promoter region
    of relevant genes to activate transcription of
    target genes.

29
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.

30
PPAR? activation.
  • Upon ligand binding, the nuclear receptor PPAR?
    associates with nuclear receptor RXR as well as
    with coactivators and corepressors which are
    present in a cell type and state specific
    pattern. This complex binds to PPAR response
    elements to enhance or repress gene transcription.

31
Biological roles of PPARa
PPARa 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.
32
Biological roles of PPARb/d
Ligand activation of PPARb/d leads to terminal
differentiation of keratinocytes as shown by four
independent laboratories. Activation of PPARb/d
in skeletal muscle leads to increased catabolism
of fatty acids and improved insulin sensitivity.
33
Biological roles of PPARg
The role of PPARg in carcinogenesis is also
controversial. There is evidence that activation
of PPARg can either potentiate or attenuate
cancer, but current consensus favors
attenuation.
34
Orchestration of Immune Responses
CELLS Lymphocytes Monocytes/Macs Neutrophils Eosin
ophils 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
35
Role of PPARa in Immune Function
  • Expressed in monocytes/macrophages, increased
    after treatment with phorbol ester
  • PPARa ligands induce apoptosis in activated
    macrophages
  • PPARa ligands decrease secretion of MMPs in
    LPS-treated monocytes
  • PPARa ligands decrease NOS activity in
    macrophages
  • BUT
  • Natural PPARa ligands increase NOS activity in
    macrophages

36
Role of PPARa in Immune Function
  • Inflammatory response induced by LTB4 is enhanced
    in PPARa-null mice
  • PPARa ligands can inhibit inflammatory cytokine
    production
  • BUT
  • PPARa ligands cause increase in serum TNFa after
    LPS

37
Role of PPARa in Immune Function
  • Reports suggest that PPARa ligands are
    anti-inflammatory but there are also some reports
    suggesting that PPARa ligands are pro-inflammatory

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Peroxisomes Inflammation
  • PPAR-a activation transcription factor for
    peroxisomal metabolism for arachidonic-derived
    proinflammatory eicosanoids.
  • ligands for this activation are the w-3 fatty
    acids, which may explain their antiinflammatory
    effects.

40
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.

41
Peroxisomes Inflammation
  • Activation of PPARs also modulates endothelial
    cell adhesion molecules, and endothelial cells
    express both PPARa and PPAR gamma

42
Peroxisomes INFLAMMATION
  • The peroxisome proliferator-activated receptors
    (PPARs) a, ß/d, and ? are ligand-activated
    transcription factors belonging to the nuclear
    receptor superfamily.
  • In addition to their regulatory role on lipid and
    glucose metabolism, they exert anti-inflammatory
    properties.
  • In skin both PPAR-a and PPAR-ß/d regulate
    keratinocyte proliferation/differentiation and
    contribute to wound healing.
  • The 3 PPAR isoforms are expressed by several cell
    types recruited into the dermis during
    inflammation.

43
Effects on angiogenesis
  • Vascular endothelial cell growth factor(VEGF) is
    a potent endothelial cell-specific 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.

44
Peroxisomes and Sterol Metabolism
  • The levels of 17b-hydroxy forms of sex steroids
    are regulated by the 17b-hydroxysteroid
    dehydrogenase (17b-
  • HSD) family of proteins.
  • The type IV enzyme, found primarily in
    peroxisomes, possesses a number of unique features

45
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

46
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.

47
Peroxisomes in Epidermal Differentiation
Proliferation
  • PPARa has a role in barrier development.
  • Activators of PPARa, 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 loricrin, a

48
Peroxisomes Atopic Dermatitis
  • Changes in immunoglobulin-associated
    transcription in atopic dermatitis may favour
  • IgE over secretory immunoglobulin (multimeric
    IgM and IgA) expression in AD skin.
  • Decreased PPAR activity appears common
  • to both AD and psoriasis, and reduced
    cutaneous IFNa2 transcription also appears
    characteristic of AD

49
Peroxisomes in Epidermal Differentiation
Proliferation
  • PPARa ligands to promote epidermal
    differentiation,to restore epidermal homeostasis
    in hyperproliferative
  • mouse epidermis and regulate apoptosis.
  • PPARb / gammainduced expression of involucrin
    and transglutaminase( markers of keratinocyte
    differentiation)

50
Wound healing
  • PPARa and PPARb / gammaexpression 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.

51
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.

52
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.

53
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.

54
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.

55
Psoriasis
  • PPAR gamma and some of its ligands, including two
    lipoxygenase metabolites, are induced by the T
    helper (TH)2 cytokine IL-4 in macrophages.
  • PPAR gamma activation may also be an integral
    part of the effecter mechanism for downregulation
    TH1 dominate inflammatory reaction such as
    psoriasis and rheumatoid arthritis

56
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

57
Psoriasis
  • There may be an association between
  • psoriasis and the genes encoding PPARa or PPAR
    gamma

58
Effects on angiogenesis
  • Vascular endothelial cell growth factor(VEGF) is
    a potent endothelial cell-specific 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.

59
Human immunodeficiencyvirus-1-protease inhibitor
associatedlipodystrophy
  • 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 PPARcRXR.
  • 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.

60
Peroxisome defects
  • 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

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64
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
    PPARa, PPARß/d and PPAR?, which have all been
    identified in keratinocytes.
  •  

65
Summary
  • PPARß/d is the predominant subtype in human
    keratinocytes, whereas PPARa and PPAR? are
    expressed at much lower levels and increase
    significantly upon keratinocyte differentiation.
  • PPARß/d is significantly upregulated upon
    various conditions that result in keratinocyte
    proliferation, and during skin wound healing.

66
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.

67
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.

68
THANK YOU
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