CORSO UNIGASTROCORSO UNIGASTROCORSO UNIGASTROCORSO UNIGASTRO San Vincenzo 4-6 Maggio 2008 CELLULE...

CORSO UNIGASTROCORSO UNIGASTROSan Vincenzo 4-6 Maggio 2008

CELLULE STELLATE EPATICHEE DANNO METABOLICO

Fabio MarraDipartimento di Medicina InternaCentro di Eccellenza “DenoTHE”

Università di FirenzeITALYITALY

Bataller & Brenner J Clin Invest 2005;115:209

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

Marra et al, Trends Mol Med 2008;14:72-81

Courtesy of SL Friedman

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

Friedman, Physiol Rev 2008;88:125

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

I li d IGF I it f HSCInsulin and IGF-I as mitogens for HSC

Svegliati Baroni et al., Hepatology 1999;29:1743

HSC express receptors for p padvanced glycation end-products

Fehrenbach et al., Hepatology 2001;34:943

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

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

The ‘fat paradox’

Tsukamoto, Keio J Med 2005;54:190

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

TLR4 inhibits TGF-β signaling via Bambi

Seki et al. Nat Med 2007;13:1324

Després & Lemieux, Nature 2006; 444:847

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

Leptin activates the mTOR pathwayp p y

Leptin induces angiogenesis and p g gneoplastic foci in vivo

Kitade et al., Hepatology 2006;44:983



FFA

Cortisol11β-HSD1

Androstenedione

EstroneEstrone


ResistinVisfatin

TNF-αMCP-1


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



FFA

Cortisol11β-HSD1

Androstenedione

EstroneEstrone


ResistinVisfatin

TNF-αMCP-1


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

Adiponectin and its receptors

Kadowaki et al., J Clin Invest 2006; 116:1784

AICARBiguanidesg

Thiazolidinediones

Modified from Long & Zierath, J Clin Invest 2006; 116:1776

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


Metformin has antifibrogenic effectsMetformin has antifibrogenic effects


Marra et al, Trends Mol Med 2008;14:72-81

CORSO UNIGASTROCORSO UNIGASTROCORSO UNIGASTROCORSO UNIGASTRO San Vincenzo 4-6 Maggio 2008 CELLULE...

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