Rosiglitazona, agonista do PPAR-γ “Peroxisome Proliferator ...
Fat and Beyond: The Diverse Biology of PPAR gamma
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Transcript of Fat and Beyond: The Diverse Biology of PPAR gamma
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WELCOME
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Fat and Beyond: The Diverse Biology of
PPARSPEAKER
P.RAMESH
PH.D
(ABC)
Credit Seminaron
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PPARs (peroxisome proliferator-activated
receptors ) are nuclear receptors & function as
“Transcription factor”
Essential roles in regulation of cellular
differentiation, atherosclerosis & macrophage
function
3 types have been identified: Alpha α, Gamma
, and Delta (Beta β)
α (alpha) - expressed in liver, kidney, heart,
muscle, adipose tissue, and others
INTRODUCTION
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β/δ (beta/delta) - expressed in many tissues but
markedly in brain, adipose tissue, and skin
γ (gamma) - although transcribed by the same
gene, this PPAR through alternative splicing is
expressed in 3 isoforms:
γ1 - expressed in virtually all tissues
γ2 - expressed mainly in adipose tissue (30
A.As longer)
γ3 - expressed in macrophages, large
intestine, white adipose tissue
Cont…
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STRUCTURE OF PPAR
PPAR is a ligand-activated transcriptional factor have
a dominant role in development of adipose cells
It is subfamily of structurally similar to nuclear
receptor
PPAR functions as an obligate heterodimer with RXRs
High affinity binding to DNA by PPAR requires
absolute dimerization with RXR
Domains of PPAR proteins present nearly all nuclear
hormone receptor Retinoid X Receptor
(Tontonoz P, et al., 1994)
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Cont…
PPAR has two N-terminal variants formed by
alternative splicing
PPAR 2 is expressed in more adipose selective
manner
N-terminal region influences the response to
ligand binding of LBD by phosphorylation at
ser112
N C
(Adams M, et al., 1997)
(Hu E, et al., 1996)
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DNA-binding domain (DBD): Highly conserved
domain containing two zinc fingers which binds
to specific sequences of DNA called hormone
response elements (HRE)
C-terminal region is responsible for dimerization
with RXR & contains Transcriptional activation
domain (AF2)
N C
(Ren D, et al., 2002)
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C-terminal region also
form ligand binding
pocket, with many
hydrophobic residuces
occuring inside the
Crystal structure
of PPAR LBD
Cont…
(Gampe RT, et al., 2000)
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PPAR activation induced by ligand dependent
and independent mechanisms
Absence of ligand, corepressors bind to
heterodimers & recruit Histone deacetylases to
repress transcription
After ligand binding, increase PPAR affinity for
number of co-activators
N-terminal regulatory domain: Contains the
activation function 1 (AF-1) whose action is
independent of the presence of ligand
Cont…
(Tontonoz P, et al., 1994)
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Co-activators: These are not themselves regulated
at expression level
CBP/p300
SRC family
TRAP220
PGC-1α
Co-repressors:
SMART
NCoR
RIP140
Co-activators,Co-repressors & Ligands
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Biological Ligands:
Polyunsaturated fatty acids
Prostanoids (15-deoxy-12,14 prostaglandin-
J2)
Leukotriene LTB4
Oxidized fattyacids (9-HODE & 13-HODE)
Lysophosphatidic acid
Synthetic Ligands:
Thiazolidinedion (TZD) Anti-Diabetic Drug
Fibrates (Hyperlipidemia)
Cont…
(Debevec D, et al., 2007)
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Adipocyte is central player in control of energy balance
& whole body lipid homeostasis
PPAR is dominant or “master” regulator of
Adipogenesis
It induces differentiation of pre-adipocytes into
adipocytes & expressed in BAT and WAT
C/EBP-β/ bind to PPAR promoter & activates PPAR
Upon ligand activation, PPAR induces many target
genes involved in Lipogenesis & Adipogenesis
PPAR & Pathway of Adipogenesis
(Sears I, et al., 1996)
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KLF15
PPAR
KLF2
KLF5
SREBP1C
KROX20 C/EBP
C/EBP C/EBP
C/EBP
CHOP
GATA2/3
Anti-adipogenic factors
Genes of Adipocytedifferentiation
Activation
Inhibition (Evan D, et al., 2006)
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PTC SMO
INSULINIGF-1
WNT10b SHH TGFFGF
BMPs
IRS
P13K
AKT/PKB
CREB
OTHERS
Testosterone
FOXO1/A2 TCF/LEF GATA2/3
-Catenin
? ?
?
C/EBP
PPAR
SMAD3 SMAD3ARP
+
SHN2SMAD1
(Evan D, et al., 2006)
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Anti-Diabetic drugsDietary fattyacids
Intracellular fattyacidsProstaglandins PGJ2
PPAR
RXR
p300SRC
CBP
RNA pol-II
Ap2
LPL
CD36
PEPCK
Aquaporin7
GLUT4
Perilipin
PGAR
GlyK
Fig: Role of PPAR pathway for Adipogenesis
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17Adipocyte
Glucose(Liver)
Triacylglycerols (Chylomicrons)
Glucose Fattyacids
Glycerol-3-P FattyacylcoA
Fattyacids
Triacylglycerols
Glycerol
HSL
Liver
LPLCD36
PerilipinPEPCK
GLUT4
Aquaporin7
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18Adipocyte
Glucose(Liver)
Triacylglycerols (Chylomicrons)
Glucose Fattyacids
Glycerol-3-P FattyacylcoA
Fattyacids
Triacylglycerols
Glycerol
HSL
Liver
LPLCD36
PerilipinPEPCK
GLUT4
Aquaporin7
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PPAR extensively studied in WAT differentiation &
same receptor is also important in BAT development
& function
Thermogenic effect of PPAR in BAT is mediated by
PGC-1α, induced by cold exposure of animals
PGC-1α regulates activation of PPAR on
thermogenesis & fattyacid oxidation by interacting
with PPAR/RXR
Stimulation of uncoupling protein (UCP-1),
responsible for uncoupling β-oxidation
Role of PPAR in Brown Adipose Tissue
PPAR Coactivator-1
(Sears I, et al., 1996)
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Phosphorylated PGC-1α is recruited PPAR
binding site on UCP-1 promoter
PGC-1α is stabilized & activated by p38 MAP
kinases
PGC-1α binds to PPAR by its LBD in a ligand
independent manner
LXXLL motif containing co-activator binds to
PPAR
Insulin/akt pathway shutdown hepatic
gluconeogenesis, phosphorylation of PGC-1
Cont…
(McInerney E, et al., 1998)
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cAMP
G protei
n
P
UCP-1
MAP kinase
PPAR
PGC-1
ATP
(Sears I, et al., 1996)
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Cont…
Fig: Thermogenesis by UCP-1 in BAT
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Insulin Resistance: is a condition in which body
cells become less sensitive to the glucose-
lowering effects of the hormone insulin
Type2 Diabetes mellitus: Pancreas secrete normal
or even greater than normal amount of insulin
Hallmark of type2 Diabetes is Insulin Resistance
In type2 Diabetes, plasma levels of FFAs &
Glucose are increased
PPAR and Insulin Resistance
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In T2DM inappropriate deposition of lipids in
liver & skeletal muscle
Thiazolidinedione (TZD), Rosiglitazone &
Pioglitazone are used for treatment of type2
Diabetes
Activation of PPAR target gene expression
enhance to store dietary fattyacids
Target genes contributing to this include AP2,
LPL, CD36, PEPCK & Aquaporin 7
(Haris P, et al., 1994)
(Kishida K, et al., 2001)
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Adipose tissue is primary target for effects of
TZD
It also promotes many signaling molecules
called Adipokines from adipocytes
Adiponectin
Resistin
TNFα
MCP-1
IL-6, IL-1β
Cont…
INFLAMMATOR
Y RESPONSE
(Bouskila M, et al., 2005)
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Ligand activation (TZD) of
PPAR in adipocytes is
associated with decreased
production of TNFα, Resistin
& MCP-1
Increase of Adiponectin gene
Decreased Insulin Resistance
Suppression of Hepatic
glucose uptake & stimulates
muscle glucose uptake
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ADIPONECTINS:
It is a protein hormone abundantly expressed in
adipocytes
Adiponectin affects:
Decreased gluconeogenesis
Increased glucose uptake
β-oxidation
Triglyceride clearance
Protection from endothelial dysfunction
insulin sensitivity
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TNF-α:
It is an inflammatory cytokine released in
obese & insulin resistance
Also propagates atherosclerotic lesion
formation
It also promotes apoptosis in endothelial
cells by dephosphorylating protein kinase
B or Akt & contribute endothelial injury
Cont…
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RESISTIN:
It is recently discovered fat-specific hormone,
directly induces insulin resistance in muscle &
liver
Neutralization of resistin by specific antibodies
results in decreased blood glucose level
It also express cell adhesion molecule (VCAM-
1), chemokine MCP-1(Atherosclerotic lesion
formation) with insulin resistance patients
Cont…
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Diet induced Obesity
Adipocyte
Adipocyte Hypertrophy
RESISTIN
?
MuscleLiverInsulin
(Olavi U, et al., 2002)
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Adipokines & Inflammation:
Increased in adipose tissue (WAT) with obesity
during inflammation (TNF-α, IL-6,IL-18, MIF, CRP &
PAI-1)
Circulatory inflammatory markers are raised in
obese
IL-6 released from adipose tissue stimulates hepatic
synthesis of CRP in obese
Similary IL-18 is acivated by TNF-α
Infiltration of Macrophages in adipose tissue(Trayhurn P, et al., 2005)
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Why Obese should be accompanied by
Inflammation???
It is mainly due to HYPOXIA
Adipose tissue (WAT) mass is very large in
Obese & Type-II diabetes are linked to
inflammation
Cont…
(Sears I, et al., 1996)
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TZD effects on Skeletal Muscle and Liver:
Skeletal Muscle is largest glucose utilizing organ,
ability of TZD is to improve whole body insulin
resistance
PPARγ expression is very low in Skeletal muscle
compare to fat
Effect of PPARγ ligands on skeletal muscle for glucose
uptake are likely to be indirect
Direct of effect of PPARγ activation in muscle is still
unclear(Castrillo A, et al., 2004)
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In liver also expression of PPARγ is very low,
activation of PPARγ signaling promotes lipid
accumulation (Hepatic Steatosis) in rodents
But does not appear in human hepatic
steatosis
TZD is beneficial in treating nonalcoholic fatty
liver disease in humans
Cont…
(Castrillo A, et al., 2004)
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PPARγ is induced differentiation of monocytes
into macrophages & highly expressed in
Macrophages
It also differentiates of monocytes into
dendritic cells
Oxidized ligands (9-HODE & 13-HODE) &
lipoproteins responsible for PPARγ signaling in
myeloid cells
Upon ligand activation, it promotes
expression of genes CD36, LXR, Arg-1& IL-10
PPAR in Inflammation
(Sears I, et al., 1996)
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PPARγ is a lipid-activated member of the nuclear
receptor superfamily of transcription factors
Biological receptor for the TZD class of
antidiabetic drugs
Master transcriptional regulator of adipocyte
differentiation & controls expression of a genes
involved in lipid metabolism
PPARγ action in myeloid cells, such as
macrophages and DCs, has been linked to the
modulation of immune and inflammatory
responses
Summary
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THANKS