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CORSO UNIGASTROCORSO UNIGASTROSan Vincenzo 4-6 Maggio 2008
CELLULE STELLATE EPATICHEE DANNO METABOLICO
Fabio MarraDipartimento di Medicina InternaCentro di Eccellenza “DenoTHE”
Università di FirenzeITALYITALY
All Roads lead to Rome!FibrosisAll Roads lead to Rome!Fibrosis
ASH NASHAIHASH NASH
HCV Iron
AIH
C
HBV
IronVascular
Biliary
Characteristics of NASH
Steatosis plus:p
Necro-inflammatory foci with mononuclear cells +/- neutrophils
Ballooning degeneration of hepatocytes +/- Mallory bodies
Pericellular fibrosis
The in vitro modelsThe in vitro models
Cultured HSC
Activated by culture on plastic 48-72 hrs after plating.
Artificial bidimensional support.pp
May be compared with cells isolated from animals with hepatic fibrosis.with hepatic fibrosis.
Gene expression in HSC isolated in vitro or in vivo
De Minicis et al., Gastroenterology 2007;132:1937
Hepatic stellate cells: the effectors of liver wound healingwound healing
Modified from Friedman, J Biol Chem 2000;275:2247-50
Modulators of stellate cell biology with relevance to NASHrelevance to NASH
InflammationOxidative stressInsulinActivation of receptors for advanced
glycation end-productsCannabinoidsNuclear hormone receptorsPattern recognition receptorsAdipokinesAdipokines
Fibrosis and inflammation: a complex relationshipFibrosis and inflammation: a complex relationship
Inflammation duringactive fibrogenesis
Expression of ROS and fibrogenic cytokines
fNK cells Antifibrogenic,kill activated HSC
Macrophages Expression of MMPsMacrophagesafter cessation of injury
Expression of MMPsand fibrosis reversal
Modulators of stellate cell biology with relevance to NASHrelevance to NASH
InflammationOxidative stressInsulinActivation of receptors for advanced
glycation end-productsCannabinoidsNuclear hormone receptorsPattern recognition receptorsAdipokinesAdipokines
HSC as targets of oxidative stress-related products
Direct effectCross talk with cytokine signalingCross-talk with cytokine signalingFormation of adducts
ROS Cytotoxic effects HNE Acetaldehyde
↑Collagen↑TIMPs↑ MCP 1
↑Collagen↑TIMP-1
↑ MCP-1↑ MMP-2↑ Migration
↑ MCP-1
↑ g↑ Proliferation
Parola et al. BBRC 1996;222:261Svegliati Baroni et al., Hepatology 1998Parola et al., J Clin Invest 1999;102:1942Nieto et al., J Biol Chem 2002; 277:9853
Modulators of stellate cell biology with relevance to NASHrelevance to NASH
InflammationOxidative stressInsulinActivation of receptors for advanced
glycation end-productsCannabinoidsNuclear hormone receptorsPattern recognition receptorsAdipokinesAdipokines
I li d IGF I it f HSCInsulin and IGF-I as mitogens for HSC
Svegliati Baroni et al., Hepatology 1999;29:1743
Modulators of stellate cell biology with relevance to NASHrelevance to NASH
InflammationOxidative stressInsulinActivation of receptors for advanced
glycation end-productsCannabinoidsNuclear hormone receptorsPattern recognition receptorsAdipokinesAdipokines
HSC express receptors for p padvanced glycation end-products
Fehrenbach et al., Hepatology 2001;34:943
Modulators of stellate cell biology with relevance to NASHrelevance to NASH
InflammationOxidative stressInsulinActivation of receptors for advanced
glycation end-productsCannabinoidsNuclear hormone receptorsPattern recognition receptorsAdipokinesAdipokines
Cannabinoid receptor activation differentiallyaffect liver fibrosis
CB1
Rimonabant
CB1
FIBROSIS
Teixeira-Clerc et al. Nat Med 2006;12:671
CB1 antagonism improves steatosisCB1 antagonism improves steatosis
Gary-Bobo et al., Hepatology 2007;46:122
Modulators of stellate cell biology with relevance to NASHrelevance to NASH
InflammationOxidative stressInsulinActivation of receptors for advanced
glycation end-productsCannabinoidsNuclear hormone receptorsPattern recognition receptorsAdipokinesAdipokines
Nuclear hormone receptors and hepatic fibrosis
Inhibitor
Stimulant
Inhibits the activated phenotype of HSCC ll
PPAR-αPPAR γ
CollagenProliferationInflammatory moleculesPPAR-γ
PPAR-β (-δ)RAR
Inhibits fibrosis in vivo but is less effective if added after the onset ofRAR
PXRFXR
effective if added after the onset of damage
FXRLXR?
Marra et al., Gastroenterology 2000;119:466Miyahara et al., J Biol Chem 2000;275:35715Galli et al., Gastroenterology 2002;122:1924Leclercq et al., Gut 2006;55:1020
Modulators of stellate cell biology with relevance to NASHrelevance to NASH
InflammationOxidative stressInsulinActivation of receptors for advanced
glycation end-productsCannabinoidsNuclear hormone receptorsPattern recognition receptorsAdipokinesAdipokines
Toll-like Pattern recognition
LPSLTA Pattern recognition
receptorsPGN
TLR4TLR2
Activation of KC and inflammatory MCP 1
PGRP-LCD14PGRP-S
TGF-β
ycells Hepatic stellate cells
MCP-1
Paik et al., Hepatology 2003;37:1043Brun et al., AJP-GI 2005 289: G571Seki et al. Nat Med 2007;13:1324
Modulators of stellate cell biology with relevance to NASHrelevance to NASH
InflammationOxidative stressInsulinActivation of receptors for advanced
glycation end-productsCannabinoidsNuclear hormone receptorsPattern recognition receptorsAdipokinesAdipokines
Adipokines: implications for fibrosis
CortisoneAndrostenedione
FFA
Cortisol11β-HSD1
Androstenedione
EstroneEstrone
Leptin Complement factorspAdipsin/D
ResistinVisfatin
TNF-αMCP-1
AngiotensinogenPAI-1 Adiponectin
MCP-1IL-6
Leptin
H2O2
ERKNF B HIF 1
H2O2Jak-StatERKp38MAPK
H2O2Jak-StatERK ERK
TIMP-1 Proliferation
PI3K/Akt
Survival Chemokines
NF-κB
VEGF
HIF-1α
Type I
p38MAPK
AP-1ERKp38MAPK PI3K/Akt
Collagen
Marra, J Hepatol 2007;46:12 2007
Leptin induces the expression of VEGF by p p yHSC via HIF-1
Control Leptin
Hypoxia
Aleffi et al., Hepatology 2005;42:1339
Adipokines: implications for fibrosis
CortisoneAndrostenedione
FFA
Cortisol11β-HSD1
Androstenedione
EstroneEstrone
Leptin Complement factorspAdipsin/D
ResistinVisfatin
TNF-αMCP-1
AngiotensinogenPAI-1 Adiponectin
MCP-1IL-6
Adipokines modulate NF-kBand MCP-1 in liver myofibroblasts
2,8 *
1,4
2,1
fold
incr
ease
)
kB kB kB Luc
0
0,7
Cnt Resistin
IL-8
(-f
*2 5y
*
IL-8
1,5
2
2,5
e ac
tivity
1
2
fold
incr
ease
)
* *0,5
1
ucife
rase
0
Cnt Rst 24 Rst 48
MC
P-1
(-f
0Control Resistin
Lu
Bertolani et al., Am J Pathol 2006; 169:2042
Cnt Rst 24 Rst 48
MCP-1
Adipokines: implications for fibrosis
CortisoneAndrostenedione
FFA
Cortisol11β-HSD1
Androstenedione
EstroneEstrone
Leptin Complement factorspAdipsin/D
ResistinVisfatin
TNF-αMCP-1
AngiotensinogenPAI-1 Adiponectin
MCP-1IL-6
Adiponectin and NASH
It is negatively correlated with obesity and the metabolic syndromemetabolic syndrome
Ameliorates glucose and lipid metabolism in g pmurine models
Reduces fibrosis in a toxic model
Inhibits activation of HSC
AMPK activation inhibits the pro-pfibrogenic phenotype of HSC
Caligiuri, Bertolani et al., Hepatology 2008;47:668
AICAR inhibits other features of the activatedAICAR inhibits other features of the activated HSC phenotype
Caligiuri, Bertolani et al., Hepatology 2008;47:668
Metformin has antifibrogenic effectsMetformin has antifibrogenic effects
Caligiuri, Bertolani et al., Hepatology 2008;47:668
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