Óvári Romane Marc Côme Julienne JPEMS students Supervisor Zsolt Bagosi MD PhD October 8 2015 Recent A dv a nces in understanding Alcoholic L iver D isease ID: 592314
Download Presentation The PPT/PDF document "Tímea" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Tímea Óvári, Romane Marc, Côme Julienne JPEMS studentsSupervisor: Zsolt Bagosi, M.D., Ph.D.October 8, 2015
Recent
A
dv
a
nces in understanding Alcoholic
L
iver
D
iseaseSlide2
Introduction to Alcoholic Liver DiseaseRole of intestinal permeability and endotoxemia in alcoholic liver diseaseRole of the hepatic
stellate cells in the alcoholic liver cirrhosisMolecular mechanisms of alcoholic fatty liverEffects of ethanol on liver regenerationInnate immune response in Alcoholic Liver DiseaseDysregulated cytokine metabolismPossible therapeutic molecules
SummarySlide3
• 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 abstinenceAlcoholic Liver Disease Slide4
Ethanol induce increasing endotoxemia3 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 Slide5
Central role of LPS – endotoxemia in ALD activate the Kupffer cells and other cells
Kupffer cell begin to produce pro-inflammatory cytokines.Slide6
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 cirrhosisSlide7
• 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)Slide8
Molecular mechanisms of alcoholic fatty liverSlide9
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 Slide10
Inhibition of PPARα by ethanolPPARα 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 RXRHigh endotoxin level in portal blood induced by ethanol decreases RXRα levels
RXR
α : Retinoïd X Receptor α (www.wikipedia.org) Slide11
Alteration of PPARα, SREBP1 and AMPK leads to steatosisAMPK : same effect as PPARα and inhibits SREBP1Ethanol reduces AMPK activity
²
²²Slide12
Effects of ethanol on liver regenerationSlide13
Different responses of a cell to an alcoholic stress Death of cells by necrosis signal for regenerationToo damaged cells start apoptosisSurviving
progenitors start repair mechanisms and then enlargement and divisionSurviving hepatocytes go into replicative senescenceResponse of a cell to a stress depend of the concentration of ROSAlcohol injuried liver can only count on progenitor cells to regenerate alcoholics are more sensible to liver injuriesSlide14
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 pathwaysSlide15
LPSIRAKCD14/TLR4
KUPFFER
STELLATET CELL1 h ↓24 h ↑Inflammatory mediators(TNF-α, IL-2, IL-8)SuperoxideETHANOLCD14/TLR4ETHANOLT celltransplantationALD
TGF-
β
collagen
production
(FIBROSIS)
Innate immune response in alcoholic liver diseasesSlide16
T CELLHEPATOCYTE
NEUTROPHIL
ROSOxidative stressIL-8IL-18SINUSOIDAL CELLSAdhesion moleculesTransmigrationCell deathDysregulated cytokine metabolismKUPFFERSTELLATE
Inflammatory
mediators
(TNF-
α
, IL-2, IL-8)
Superoxide
LPSSlide17
KUPFFERT CELLETHANOL
collagen
production(FIBROSIS)Resistance:Deficiency in CD14/TLR4 pathwayDeficiency in TNF-α receptor 1Deficiency in p47phox (NADPH oxidase)Non-absorbable antibioticsProbioticsAnti-TNF-α AbAdenoviral overexpression of SODGadolinium chlorideAntioxidantsTGF-βSTELLATEInflammatory
mediators
(TNF-
α
, IL-2, IL-8)
Superoxide
LPS
Possible
therapeutic
moleculesSlide18
Thank you for your attention!Tímea Óvári
,
Romane Marc, Côme Julienne Acknowledgement:Supervisor: Zsolt Bagosi M.D. Ph.D.Department of Pathophysiology, University of SzegedProfessor Dr. habil Gyula Szabó, M.D., Ph.D., D.Sc.Professor Dr. habil Márta Széll M.D., Ph.D.