CELLULE STELLATE EPATICHE E DANNO METABOLICO. Fabio Marra Dipartimento di Medicina Interna Centro di Eccellenza DenoTHE Università di Firenze

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1 CORSO UNIGASTRO San Vincenzo 4-6 Maggio 2008 CELLULE STELLATE EPATICHE E DANNO METABOLICO Fabio Marra Dipartimento di Medicina Interna Centro di Eccellenza DenoTHE Università di Firenze ITALY

2 Bataller & Brenner J Clin Invest 2005;115:209

3 All Roads lead to Rome! Fibrosis ASH AIH NASH HCV HBV Biliary Iron Vascular

4 Characteristics of NASH Steatosis plus: Necro-inflammatory foci with mononuclear cells +/- neutrophils Ballooning degeneration of hepatocytes +/- Mallory bodies Pericellular fibrosis

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

6 Courtesy of SL Friedman

7 The in vitro models Cultured HSC Activated by culture on plastic hrs after plating. Artificial bidimensional support. May be compared with cells isolated from animals with hepatic fibrosis.

8 Gene expression in HSC isolated in vitro or in vivo De Minicis et al., Gastroenterology 2007;132:1937

9 Hepatic stellate cells: the effectors of liver wound healing Modified from Friedman, J Biol Chem 2000;275:

10 Modulators of stellate cell biology with relevance to NASH Inflammation Oxidative stress Insulin Activation of receptors for advanced glycation end-products Cannabinoids Nuclear hormone receptors Pattern recognition receptors Adipokines

11 Fibrosis and inflammation: a complex relationship Inflammation during active fibrogenesis Expression of ROS and fibrogenic cytokines NK cells Antifibrogenic, kill activated HSC Macrophages after cessation of injury Expression of MMPs and fibrosis reversal

12 Friedman, Physiol Rev 2008;88:125

13 Modulators of stellate cell biology with relevance to NASH Inflammation Oxidative stress Insulin Activation of receptors for advanced glycation end-products Cannabinoids Nuclear hormone receptors Pattern recognition receptors Adipokines

14 HSC as targets of oxidative stress-related products Direct effect Cross-talk with cytokine signaling Formation of adducts ROS Cytotoxic effects HNE Acetaldehyde Collagen TIMPs MCP-1 MMP-2 Migration Proliferation Collagen TIMP-1 MCP-1 Parola et al. BBRC 1996;222:261 Svegliati Baroni et al., Hepatology 1998 Parola et al., J Clin Invest 1999;102:1942 Nieto et al., J Biol Chem 2002; 277:9853

15 Modulators of stellate cell biology with relevance to NASH Inflammation Oxidative stress Insulin Activation of receptors for advanced glycation end-products Cannabinoids Nuclear hormone receptors Pattern recognition receptors Adipokines

16 Insulin and IGF-I I as mitogens for HSC Svegliati Baroni et al., Hepatology 1999;29:1743

17 Modulators of stellate cell biology with relevance to NASH Inflammation Oxidative stress Insulin Activation of receptors for advanced glycation end-products Cannabinoids Nuclear hormone receptors Pattern recognition receptors Adipokines

18 HSC express receptors for advanced glycation end-products Fehrenbach et al., Hepatology 2001;34:943

19 Modulators of stellate cell biology with relevance to NASH Inflammation Oxidative stress Insulin Activation of receptors for advanced glycation end-products Cannabinoids Nuclear hormone receptors Pattern recognition receptors Adipokines

20 Cannabinoid receptor activation differentially affect liver fibrosis Rimonabant CB1 FIBROSIS Teixeira-Clerc et al. Nat Med 2006;12:671

21 CB1 antagonism improves steatosis Gary-Bobo et al., Hepatology 2007;46:122

22 Modulators of stellate cell biology with relevance to NASH Inflammation Oxidative stress Insulin Activation of receptors for advanced glycation end-products Cannabinoids Nuclear hormone receptors Pattern recognition receptors Adipokines

23 Nuclear hormone receptors and hepatic fibrosis Inhibitor Stimulant PPAR-α PPAR-γγ PPAR-β (-δ) RAR PXR FXR LXR? Inhibits the activated phenotype of HSC Collagen Proliferation Inflammatory molecules Inhibits fibrosis in vivo but is less effective if added after the onset of damage Marra et al., Gastroenterology 2000;119:466 Miyahara et al., J Biol Chem 2000;275:35715 Galli et al., Gastroenterology 2002;122:1924 Leclercq et al., Gut 2006;55:1020

24 The fat paradox Tsukamoto, Keio J Med 2005;54:190

25 Modulators of stellate cell biology with relevance to NASH Inflammation Oxidative stress Insulin Activation of receptors for advanced glycation end-products Cannabinoids Nuclear hormone receptors Pattern recognition receptors Adipokines

26 LPS LTA PGN Toll-like Pattern recognition receptors Activation of KC and inflammatory cells MCP-1 TGF-β Hepatic stellate cells TLR4 TLR2 PGRP-L CD14 PGRP-S Paik et al., Hepatology 2003;37:1043 Brun et al., AJP-GI : G571 Seki et al. Nat Med 2007;13:1324

27 TLR4 inhibits TGF-β signaling via Bambi Seki et al. Nat Med 2007;13:1324

28 Modulators of stellate cell biology with relevance to NASH Inflammation Oxidative stress Insulin Activation of receptors for advanced glycation end-products Cannabinoids Nuclear hormone receptors Pattern recognition receptors Adipokines

29 Després & Lemieux, Nature 2006; 444:847

30 Adipokines: implications for fibrosis Cortisone 11β-HSD1 Cortisol FFA Androstenedione Estrone Leptin Complement factors Adipsin/D Visfatin Angiotensinogen PAI-1 TNF-α MCP-1 IL-6 Resistin Adiponectin

31 Leptin H 2 O 2 Jak-Stat ERK p38 MAPK AP-1 H 2 O 2 Jak-Stat ERK p38 MAPK ERK PI3K/Akt ERK PI3K/Akt NF-κB HIF-1α Type I Collagen TIMP-1 Proliferation Survival Chemokines VEGF Marra, J Hepatol 2007;46:

32 Leptin induces the expression of VEGF by HSC via HIF-1 Control Leptin Hypoxia Aleffi et al., Hepatology 2005;42:1339

33 Leptin activates the mtor pathway

34 Leptin induces angiogenesis g and neoplastic foci in vivo Kitade et al., Hepatology 2006;44:983

35 Adipokines: implications for fibrosis Cortisone 11β-HSD1 Cortisol FFA Androstenedione Estrone Leptin Complement factors Adipsin/D Visfatin Angiotensinogen PAI-1 TNF-α MCP-1 IL-6 Resistin Adiponectin

36 Adipokines modulate NF-kB and MCP-1 in liver myofibroblasts 2,8 * fold increase) 2,1 1,4 kb kb kb Luc IL-8 (-f MCP-1 (-f fold increase) 0, Cnt Resistin IL-8 * * Cnt Rst 24 Rst 48 Lu uciferase e activity 25 2,5 2 1,5 1 0,5 0 * Control Resistin MCP-1 Bertolani et al., Am J Pathol 2006; 169:2042

37 Adipokines: implications for fibrosis Cortisone 11β-HSD1 Cortisol FFA Androstenedione Estrone Leptin Complement factors Adipsin/D Visfatin Angiotensinogen PAI-1 TNF-α MCP-1 IL-6 Resistin Adiponectin

38 Adiponectin and NASH It is negatively correlated with obesity and the metabolic syndrome Ameliorates glucose and lipid metabolism in murine models Reduces fibrosis in a toxic model Inhibits activation of HSC

39 Adiponectin and its receptors Kadowaki et al., J Clin Invest 2006; 116:1784

40 AICAR Biguanides Thiazolidinediones Modified from Long & Zierath, J Clin Invest 2006; 116:1776

41 AMPK activation inhibits the pro- fibrogenic phenotype of HSC Caligiuri, Bertolani et al., Hepatology 2008;47:668

42 AICAR inhibits other features of the activated HSC phenotype Caligiuri, Bertolani et al., Hepatology 2008;47:668

43 Metformin has antifibrogenic effects Caligiuri, Bertolani et al., Hepatology 2008;47:668

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