Transcript Role of intestinal permeability and endotoxemia in alcoholic

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
Summary
1.
2.
3.
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
4.
5.
Molecular mechanisms of alcoholic fatty liver
Effects of ethanol on liver regeneration
6.
7.
8.
Innate immune response in Alcoholic Liver Disease
Dysregulated cytokine metabolism
Possible therapeutic molecules
Alcoholic Liver Disease
• Steatosis : Lipid
accumulation.
Reversible
process.
• Hepatitis : inflammation in the
liver  leads to cell injury.
Symptoms : jaundice, fever, pain.
Recovery in 10-50% of cases if
alcohol abstinence
• 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.
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
(R. K. Rao, A. Seth, P. Sheth , 2004)
MLCK : myosine light chain kinase
TJ : 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.
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
Retinol absorbtion
• Liver sinusoidal endothelial cells
 defenestration  lack of retinol
Defenestration of the
sinusoid hepatic cells
• Kuppfer cells
pro-inflammatory cytokines
- TGFß : fibrogenic factor
Hepatocyte
Lack of retinol
Stellate cell ( Ito cell)
à Storage
Differentiation
- 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
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
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
(www.wikipedia.org)
RXRα : Retinoïd X Receptor α
Alteration of PPARα, SREBP1 and AMPK leads to steatosis
²
• AMPK : same effect as
PPARα
and
inhibits
SREBP1
• Ethanol reduces AMPK
activity
²
²
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
ETHANOL
Innate immune response in alcoholic liver diseases
ALD
LPS
CD14/TLR4
1h↓
24 h ↑
IRAK
KUPFFER
T cell
transplantation
• Inflammatory
mediators
(TNF-α, IL-2, IL-8)
• Superoxide
ETHANOL
CD14/TLR4
TGF-β
T CELL
STELLATE
collagen production
(FIBROSIS)
Dysregulated cytokine metabolism
LPS
SINUSOIDAL
CELLS
Adhesion molecules
KUPFFER
NEUTROPHIL
ROS
IL-8
IL-18
Oxidative
stress
HEPATOCYTE
Transmigration
• Inflammatory
mediators
(TNF-α, IL-2, IL-8)
• Superoxide
Cell
death
STELLATE
T CELL
Possible therapeutic molecules
LPS
Gadolinium chloride
Resistance:
• Deficiency in CD14/TLR4 pathway
• Deficiency in TNF-α receptor 1
• Deficiency in p47phox (NADPH oxidase)
Antioxidants
KUPFFER
• Non-absorbable
antibiotics
• Probiotics
• Inflammatory
mediators
(TNF-α, IL-2, IL-8)
• Superoxide
• Anti-TNF-α Ab
• Adenoviral
overexpression
of SOD
T CELL
ETHANOL
TGF-β
STELLATE
collagen production
(FIBROSIS)
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.