Tímea Óvári, Romane Marc, Côme Julienne JPEMS students

Supervisor: Zsolt Bagosi, M.D., Ph.D.October 8, 2015

Recent Advances in understanding Alcoholic Liver Disease

1. Introduction to Alcoholic Liver Disease

2. Role of intestinal permeability and endotoxemia in alcoholic liver disease

3. Role of the hepatic stellate cells in the alcoholic liver cirrhosis

4. Molecular mechanisms of alcoholic fatty liver

5. Effects of ethanol on liver regeneration

6. Innate immune response in Alcoholic Liver Disease

7. Dysregulated cytokine metabolism

8. Possible therapeutic molecules

Summary

• Steatosis : Lipid accumulation.

Reversible process.

• Cirrhosis : Chronic inflammation induce fibrosis process : production of collagen. Surviving hepatocytes try to regenerate the hepatic parenchyma regenerative nodule formation.Complications : portal hypertension, liver failure and ascite formation.Irreversibility.

• Hepatitis : inflammation in the liver leads to cell injury.Symptoms : jaundice, fever, pain. Recovery in 10-50% of cases if alcohol abstinence

Alcoholic Liver Disease

Ethanol induce increasing endotoxemia

• 3 hypothesis :

(R. K. Rao, A. Seth, P. Sheth , 2004)

Role of intestinal permeability and endotoxemia in alcoholic liver disease

The localization of the disruption seems to be correlate with the type of use : - Acute duodenal localization - Chronic intestinal localization +++

Tight junction disruption

MLCK : myosine light chain kinaseTJ : tight junction AJ : adherence junction

Central role of LPS – endotoxemia in ALD

activate the Kupffer cells and other cells Kupffer cell begin to produce pro-inflammatory cytokines.

2. Stellate cell : key role in the fibrogenesis

• Liver sinusoidal endothelial cells• Kuppfer cells• Hepatocytes • Autocrin loop auto-activation

Activation of hepatic stellate cell involve all components of the liver after alcohol exposure :

1. Physiological role of the stellate cells

• Quiescent cells : storage of retinol• Located in the Disse space

Role of the hepatic stellate cells in the alcoholic liver cirrhosis

• Liver sinusoidal endothelial cells defenestration lack of retinol

• Kuppfer cellspro-inflammatory cytokines- TGFß : fibrogenic factor- PDGF : mitogenic factor

• Injured hepatocytes produce ROS

• Autocrin loop : activated stellate cell produce their own TNF alpha and TGFß accelerate the differentiation.

(Guo and Friedmana, 2010)

Molecular mechanisms of alcoholic fatty liver

Ethanol decreases oxidation of the lipids by distorting PPARα, and increases lipogenesis by modifying SRBP1.

PPARα : Peroxysome proliferator activating receptor αSREBP1 : Sterol regulatory element binding protein 1

Two main pathways

Inhibition of PPARα by ethanol

• PPARα is a nuclear receptor which stimulates transcription of genes involved in free fatty acid transport and oxidation. To be activated it has to dimerize with RXR

• High endotoxin level in portal blood induced by ethanol decreases RXRα levels

RXRα : Retinoïd X Receptor α

(www.wikipedia.org)

Alteration of PPARα, SREBP1 and AMPK leads to steatosis

• AMPK : same effect as PPARα and inhibits SREBP1

• Ethanol reduces AMPK activity

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Effects of ethanol on liver regeneration

Different responses of a cell to an alcoholic stress

• Death of cells by necrosis signal for regeneration

• Too damaged cells start apoptosis• Surviving progenitors start repair

mechanisms and then enlargement and division

• Surviving hepatocytes go into replicative senescence

• Response of a cell to a stress depend of the concentration of ROS

• Alcohol injuried liver can only count on progenitor cells to regenerate alcoholics are more sensible to liver injuries

Liver stem cells

• Little is known about liver stem cells

• Come from the liver ? Fusion of myeloid progenitor and resident liver cells ?

• Injured progenitor cells express Notch and Jagged factors showing a reactivation of foetal pathways

LPS

IRAK

CD14/TLR4

KUPFFER

STELLATE

T CELL

1 h ↓24 h ↑

• Inflammatory mediators(TNF-α, IL-2, IL-8)

• Superoxide

ETHANOL

CD14/TLR4 ETHANOL

T celltransplantation

ALD

TGF-β

collagen production(FIBROSIS)

Innate immune response in alcoholic liver diseases

T CELLHEPATOCYTE

NEUTROPHIL

ROS

Oxidative stress

IL-8IL-18

SINUSOIDAL CELLS

Adhesion molecules

Transmigration

Cell death

Dysregulated cytokine metabolism

KUPFFER

STELLATE

• Inflammatory mediators(TNF-α, IL-2, IL-8)

• Superoxide

LPS

KUPFFER

T CELL

ETHANOL

collagen production(FIBROSIS)

Resistance:• Deficiency in CD14/TLR4 pathway• Deficiency in TNF-α receptor 1• Deficiency in p47phox (NADPH oxidase)

• Non-absorbable antibiotics

• Probiotics

• Anti-TNF-α Ab• Adenoviral

overexpression of SOD

Gadolinium chloride

Antioxidants

TGF-β STELLATE

• Inflammatory mediators(TNF-α, IL-2, IL-8)

• Superoxide

LPS

Possible therapeutic molecules

Thank you for your attention!Tímea Óvári, Romane Marc, Côme Julienne

Acknowledgement:

Supervisor: Zsolt Bagosi M.D. Ph.D.Department of Pathophysiology, University of Szeged

Professor Dr. habil Gyula Szabó, M.D., Ph.D., D.Sc.Professor Dr. habil Márta Széll M.D., Ph.D.