Steatosi, infiammazione e fibrosi: meccanismi patogenetici e interazioni

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1 Steatosi, infiammazione e fibrosi: meccanismi patogenetici e interazioni Fabio Marra Dipartimento di Medicina Sperimentale e Clinica University of Florence, Italy [email protected]

2 Female, 72 years old, caucasian (born 1940) Obesity since young age 1970: diagnosis of type 2 diabetes, initially treated with oral antidiabetic medications, switched to insulin in 1992 due to poor glyco-metabolic control. 1992: Diagnosis of Hypertension, treated with ACE inhibitors and then ARB 1998: Diagnosis of Hypercholesterolemia 2005: Discovery of a cold thyroid nodule (stable on follow-up) Never smoked Never consumed alcohol 2000: diagnosis of hepatic steatosis. ALT and GGT reported to be occasionally elevated but predominantly within normal range The patient has since then occasionally performed abdominal US scans without a definite time interval.

3 January 2012: The patient performs an abdominal US scan because of dull, upper right quadrant, abdominal pain: In the context of an enlarged bright liver possibly due to fatty infiltration, there is a large mass (approximately 10cm) constituted by confluent nodules, localized in the VIII, VII, VI segments. No spleen enlargement. No ascites. Evaluated in a different Unit in the hypothesis of hepatic metastases: Normal CEA, CA 19.9, Ca125, CA72.4 Upper GI endoscopy: no alterations, specifically no signs of portal hypertension Colonoscopy: diverticulosis of sigmoid colon. CT scan: no alterations of pancreas Referred to our Unit for further testing

4 US-guided biopsy of hepatic nodule: trabecular hepatocellular carcinoma NASH-related fibrosis without cirrhosis

5 SIMPLE STEATOSIS INSULIN RESISTANCE STEATOHEPATITIS CIRRHOSIS Hepatic decompensation HEPATOCELLULAR CARCINOMA DEATH

6 Pathogenesis of fatty liver Marra & Lotersztajn, Curr Pharm Des 2013

7 SIMPLE STEATOSIS STEATOHEPATITIS Pathology-based definition Hepatocellular damage (ballooning) Inflammation Fibrosis CIRRHOSIS Hepatic decompensation HEPATOCELLULAR CARCINOMA DEATH

8 Definition of lipotoxicity Steatosis A condition whereby fat accumulation results toxic effects on the cell and causes damage or death Steatosis and damage (steatohepatitis) LIPOTOXICITY Fatty acids

9 INSULIN RESISTANCE HEPATIC FATTY ACID OVERLOAD LIPOTOXICITY bad storers STEATOHEPATITIS? TG ACCUMULATION good storers SIMPLE STEATOSIS CIRRHOSIS Hepatic decompensation HEPATOCELLULAR CARCINOMA DEATH

10 FFA Adipokine imbalance Inflammatory cytokines Bacterial products Specific nutrients KC IC TNF IL-1β CCL2 TGF-β ROS JNK NF-κB ER stress Hep HSC Fibrosis

11 Fibrosis Steatosis Hepatic stellate cell activation Apoptosis & ER stress Oxidative stress Inflammation Autophagy Steatosis and damage) (LIPOTOXICITY) Nuclear receptors Cannabinoids

12 ER stress and apoptosis Malhi & Kaufman J Hepatol 2011;54:795

13 Fibrosis Steatosis Hepatic stellate cell activation Apoptosis & ER stress Oxidative stress Inflammation Autophagy Steatosis and damage) (LIPOTOXICITY) Nuclear receptors Cannabinoids

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15 HSC as targets of oxidative stress-related products Direct effect Cross-talk with cytokine signaling Formation of adducts ROS Cytotoxic effects HNE 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

16 Fibrosis Steatosis Hepatic stellate cell activation Apoptosis & ER stress Oxidative stress Inflammation Autophagy Steatosis and damage) (LIPOTOXICITY) Nuclear receptors Cannabinoids

17 Initial biopsy inflammation grade predicts progression to advanced fibrosis Argo et al., J Hepatol 2009; 51:371

18 Pink Floyd, 1975

19 Marra & Lotersztajn, Curr Pharm Des 2013

20 The inflammasomes Schroder & Tschopp Cell 2010;140, 821

21 The concept of sterile inflammation Kubes & Mehal, Grastroenterology 2012

22 The inflammasome pathway is activated in the MCD model of NASH Csak et al., Hepatology 2011;54:133

23 Inflammasome deficiency protects from insulin resistance and steatosis Stienstra et al., PNAS 2011;108:15324

24 Inflammasome deficiency worsens NASH interacting with the microbiome Henao-Mejia et al., Nature 2012; 482:179

25 Fibrosis Steatosis Hepatic stellate cell activation Apoptosis & ER stress Oxidative stress Inflammation Autophagy Steatosis and damage) (LIPOTOXICITY) Nuclear receptors Cannabinoids

26 Autophagy: a new player in liver diseases Amir and Czaja, Expert Rev Gastroneterol Hepatol 2011

27 Fibrosis Steatosis Hepatic stellate cell activation Apoptosis & ER stress Oxidative stress Inflammation Autophagy Steatosis and damage) (LIPOTOXICITY) Nuclear receptors Cannabinoids

28 The dual PPARα/δ agonist GFT505 in models of NAFLD/NASH Staels et al., Hepatology 2013

29 The Farnesoid X Receptor Agonist Obeticholic Acid in NAFLD Mudaliar et al., Gastroenterology 2013

30 Fibrosis Steatosis Hepatic stellate cell activation Apoptosis & ER stress Oxidative stress Inflammation Autophagy Steatosis and damage) (LIPOTOXICITY) Nuclear receptors Cannabinoids

31 Patti. J Clin Invest. 2010;120:2646

32 FFA Adipokine imbalance Inflammatory cytokines Bacterial products Specific nutrients KC IC TNF IL-1β CCL2 TGF-β ROS JNK NF-κB ER stress Hep HSC Fibrosis

33 iron copper Saturated FA Lipotoxicity ROS Inflammation LPS Fructose Steatosis AGE n-3 PUFA Cholesterol Marra & Lotersztajn, Curr Pharm Des 2013

34 Singh, Cell 2007;130:765

35 Effecs of curcumin on Fibrogenesis PPAR-γ Oxidative stress

36 Inflammasome activation Berberine Kubes& Mehal, Grastroenterology 2012

37 FFA Adipokine imbalance Inflammatory cytokines Bacterial products Specific nutrients KC IC TNF IL-1β CCL2 TGF-β ROS JNK NF-κB ER stress Hep HSC Fibrosis

38 Inflammation and immunity in obesity Lumeng, JCI 2011

39 Adipose tissue changes after weight gain FFA Treg TNF-α IL-1β CCL2 OPN inos Adipose tissue IR Lipolysis M1 Leptin Adiponectin CCL2 M1 M2 Weight gain M2 Treg Apoptosis Hypoxia Lean Obese Marra & Lotersztajn, Curr Pharm Des 2013

40 Marra & Bertolani, Hepatology 2009;50:957

41 Myostatin HSC TGF-beta-like effects: Autoinduction of TGF-beta TIMP-1 Collagen Growth arrest Smad3 phosphorylation Chemotaxis

42 Zimmer & Lammert, Best Pract Res Clin Gastroenterol 2011

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