1. Recent Advances in understanding Alcoholic Liver Disease
Tímea Óvári, Romane Marc, Côme Julienne
JPEMS students
Supervisor: Zsolt Bagosi, M.D., Ph.D.
October 8, 2015

2. Summary Introduction to Alcoholic Liver Disease
Role of intestinal permeability and endotoxemia in alcoholic liver disease
Role of the hepatic stellate cells in the alcoholic liver cirrhosis
Molecular mechanisms of alcoholic fatty liver
Effects of ethanol on liver regeneration
Innate immune response in Alcoholic Liver Disease
Dysregulated cytokine metabolism
Possible therapeutic molecules

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

4. Ethanol induce increasing endotoxemia
Role of intestinal permeability and endotoxemia in alcoholic liver disease
Ethanol induce increasing endotoxemia
3 hypothesis :
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 kinase
TJ : tight junction
AJ : adherence junction
(R. K. Rao, A. Seth, P. Sheth , 2004)

5. Central role of LPS – endotoxemia in ALD
 activate the Kupffer cells and other cells  Kupffer cell begin to produce pro-inflammatory cytokines.

6. 2. Stellate cell : key role in the fibrogenesis
Role of the hepatic stellate cells in the alcoholic liver cirrhosis
1. Physiological role of the stellate cells
• Quiescent cells : storage of retinol
• Located in the Disse space
2. Stellate cell : key role in the fibrogenesis
Activation of hepatic stellate cell involve all components of the liver after alcohol exposure :
• Liver sinusoidal endothelial cells
• Kuppfer cells
• Hepatocytes
• Autocrin loop  auto-activation

7. • Liver sinusoidal endothelial cells  defenestration  lack of retinol • Kuppfer cells pro-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)

8. Molecular mechanisms of alcoholic fatty liver

9. Two main pathways
Ethanol decreases oxidation of the lipids by distorting PPARα, and increases lipogenesis by modifying SRBP1.
PPARα : Peroxysome proliferator activating receptor α
SREBP1 : Sterol regulatory element binding protein 1

10. 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

11. Alteration of PPARα, SREBP1 and AMPK leads to steatosis
AMPK : same effect as PPARα and inhibits SREBP1
Ethanol reduces AMPK activity

12. Effects of ethanol on liver regeneration

13. 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

14. 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

15. Innate immune response in alcoholic liver diseases
ETHANOL
Innate immune response in alcoholic liver diseases
ALD
LPS
CD14/TLR4
KUPFFER
1 h ↓ 24 h ↑
IRAK
T cell
transplantation
Inflammatory mediators (TNF-α, IL-2, IL-8)
Superoxide
T CELL
Kupffer cells are the main effectors of innate immune response in ALD. They are activated by gut-derived endotoxin.
ETHANOL
CD14/TLR4
TGF-β
STELLATE
collagen production
(FIBROSIS)

16. Dysregulated cytokine metabolism
LPS
SINUSOIDAL CELLS
Adhesion molecules
KUPFFER
NEUTROPHIL
ROS
Transmigration
Oxidative stress
IL-8
IL-18
Inflammatory mediators (TNF-α, IL-2, IL-8)
Superoxide
T CELL
HEPATOCYTE
Cell death
STELLATE

17. Possible therapeutic molecules
Resistance:
Deficiency in CD14/TLR4 pathway
Deficiency in TNF-α receptor 1
Deficiency in p47phox (NADPH oxidase)
LPS
Gadolinium chloride
Antioxidants
KUPFFER
Anti-TNF-α Ab
Adenoviral overexpression of SOD
Inflammatory mediators (TNF-α, IL-2, IL-8)
Superoxide
Non-absorbable antibiotics
Probiotics
T CELL
Kupffer cells are the main effectors of innate immune response in ALD. They are activated by gut-derived endotoxin.
ETHANOL
TGF-β
STELLATE
collagen production
(FIBROSIS)

18. 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.