Peroxisome proliferatoractivated receptors

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Peroxisome proliferator-activated receptors in
health and disease
Jeffrey M. Peters Associate Professor Center for
Molecular Toxicology and Carcinogenesis, The
Pennsylvania State University, University Park, PA

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Hepatic Peroxisome Proliferation
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PPARs

• Nuclear hormone receptor superfamily
• Multiple isoforms (?, ? (d), ?)
• Unique tissue distribution

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Sequence Comparison of PPARS
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PPAR Activators/Ligands
PPAR? Fatty acids (derivatives), hypolipidemic
drugs (fibrates, Wy-14,643), industrial
solvents/plasticizers (pthalates) PPAR?
Prostaglandin J2, thiozoladinediones
(troglitazone, etc) PPAR?/d Fatty acids,
fatty acid derivatives (L-165,041, GW1516, GW0742)
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Activation of PPARs by Phthalate Monoesters
There is a large species difference in the
concentration of phthalate monoesters required to
activate PPARs. Bility, M. et al, Tox. Sci., 2004
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Mechanism of PPAR action
?
Co-repressors Co-activators
PPARRXR?
?
?
Modulation of gene transcription
Biological effect
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Mechanism of PPAR action
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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.
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Biological roles of PPARa
PPARa mediates the hepatocarcinogenic effect
induced by peroxisome proliferators in rodents,
human relevance is questionable.
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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.
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Biological roles of PPARb/d
The role of PPARb/d in carcinogenesis is
controversial. There is evidence that activation
of PPARb/d can either potentiate or attenuate
cancer.
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Biological roles of PPARg
Activation of PPARg leads to improved insulin
sensitivity and lower serum glucose during
hyperglycemia. Basis for therapeutic use as
anti-diabetic drugs.
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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.
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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
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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

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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

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Role of PPARa in Immune Function

• More 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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Role of PPARa in Immune Function

• PPARa mediates ligand induced decrease in T-cells
  and B-cells.
• Alternative mechanism of anti-inflammatory action?

Yang, Q. et al Biochem. Pharm. 2002
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Role of PPARb/d in Immune Function

• PPARb/d is expressed in many immune cell types,
  is induced in macrophages by phorbol ester

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Role of PPARb/d in Immune Function

• Enhanced neutrophil accumulation in TPA-treated
  PPARb/d-null (/) mouse skin suggests that
  PPARb/d is anti-inflammatory

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Role of PPARb/d in Immune Function

• PPARb/d ligand inhibits myeloperoxidase activity,
  independent of the receptor

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Role of PPARb/d in Immune Function

• Inhibition of MPO activity by all three PPAR
  ligands

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Role of PPARb/d in Immune Function

• PPARb/d ligand inhibits LPS-stimulated iNOS, COX2
  and TNFa in macrophages
• Welch, J et al, PNAS, 2003

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Role of PPARb/d in Immune Function

• PPARb/d ligands are anti-inflammatory, some of
  these effects are independent of the receptor.

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Role of PPARg in Immune Function

• PPARg is expressed in macrophages and splenic
  dendritic cells
• PPARg ligands inhibit inflammatory cytokines in
  macrophages and monocytes
• BUT..
• PPARg ligands up-regulate pro-inflammatory
  surface receptors (CD14, CD11b/CD18, SRB1)

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Role of PPARg in Immune Function

• Inhibition of iNOS and IL-6 in macrophages by
  PPARg ligand (rosiglitazone) is dependent on
  PPARg at 10 µM but not at 50 µM.
  Welch, J et al, PNAS, 2003

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Role of PPARg in Immune Function

• PPARg ligands inhibit antigen-stimulated
  responses of T-cell clones
• PPARg ligands mediate inhibition of anti-CD3
  antibody-stimulated proliferative responses of
  T-cell clones and freshly isolated enriched
  splenocytes
• The mechanisms underlying these responses are
  unclear but could involve inhibition of IL-2
  secretion and/or apoptosis
• Clark, R, et al J. Immun. 2000
• Yang, X, et al JBC, 2000
• Harris, SG, et al, Eur. J. Immun., 2001

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Role of PPARg in Immune Function

• PPARg ligands also inhibit B-cell growth
• Padilla, J, et al J. Immun. 2000

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Summary

• Activation of PPARa is used therapeutically
  because it can reduce serum lipids.
• Activation of PPARg is used therapeutically
  because it increases insulin sensitivity
• Activation of PPARb/d is being explored as a
  mechanism to increase insulin sensitivity
• Activation of PPARa causes hepatocarcinogenesis
• Controversial literature regarding the role of
  PPARb/d and PPARg in cancer

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Summary

• While there are highly specific ligands for all
  three PPARs, there is accumulating evidence that
  there are off-site targets for these ligands
  (e.g. inhibition of MPO, etc). Null mouse studies
  will be useful for determining off-site
  targets.
• There is good evidence that ligands for all three
  PPARs are anti-inflammatory, and some of these
  effects may be mediated by the receptor (e.g.
  interaction with NF-kB, etc) or independent of
  the receptor (e.g. off-site targets, etc).
• PPARa/g ligands can influence T-cells and
  B-cells, role of these changes on immune function
  uncertain.

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Human Relevance

• Hepatocarcinogenic effect of PPARa ligands
  appears to be rodent-specific.
• Null mouse studies clearly demonstrate receptor
  requirement, but there can be differences in
  receptor function between species.
• PPARg ligands (rosiglitazone and pioglitazone)
  are currently being used as anti-diabetic agents,
  on-going analysis may provide clues for role of
  ligands/receptor on cancer, immune function.
• Clinical trials have also been performed to
  examine efficacy of PPARg ligands to inhibit
  carcinogenesis.
• PPARb/d ligands are being developed, effect in
  humans currently unclear.