barcelona . spain - European Association for the Study of the Liver

BARCELONA . SPAIN
40 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 41
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
(IL10). Defective secretion of IL10 by blood monocytes is associated with TNF-α overproduction in patients
with severe alcoholic hepatitis, that is likely to worsen inflammation and promote ALD progression. Moreover,
alcohol down regulates adiponectin and the AMPK/sirtuin1 pathway, which display potent antiinflammatory
properties for Kupffer cells.
T Helper lymphocyte 17 (Th17). Th17 lymphocytes are a recently described class of CD4+ lymphocytes
that produce interleukin 17 (IL17) and interleukin 22 (IL22). Differenciation of naïve CD4+ lymphocytes into
Th17 cells is promoted by IL6 and IL1, that are overproduced by Kupffer cells during ALD. Plasma levels
of IL17 and the number of infiltrating IL17 secreting cells in the liver are increased in patients with ALD.
IL17 promotes neutrophil recruitment by enhancing the production of chemoattractants (IL8 and GRO-α)
by hepatic stellate cells (8).
Neutrophil recruitment. Migration of neutrophils into the liver is a major inflammatory event in patients
with alcoholic steatohepatitis. In addition to IL17, accumulation of neutrophils is promoted by Kupffer cellderived
cytokines and chemokines that are markedly up-regulated in patients with ALD such as TNF, IL1
and CXC chemokines (1, 4, 5).
Oxidative stress (Figure 3). Increased oxidative stress and reduced antioxidant defense mechanisms
are key features of alcoholic steatohepatitis in humans, and play a key role in hepatocellular injury (9).
Hepatocytes and Kupffer cells are major sources of reactive oxygen species in response to chronic alcohol
exposure, produced by cytochrome P450 2E1, NADP(H)oxidase, and inducible nitric oxide synthase.
Increase in oxidative stress causes mitochondrial damage and lipid peroxidation and decrease proteasome
activity, resulting in increased hepatocellular apoptosis. Hepatocellular injury is further amplified by a
decrease in antioxidant defense mechanisms, since alcohol depletes mitochondrial glutathione. Depletion
of S-adenosyl methionine (SAM) by alcohol contributes to reduction of glutathion levels, because SAM is
a precursor for glutathione, and increase in endoplasmic reticlum stress, both pathways contributing to
hepatocellular injury. In addition, reactive oxygen species produced by Kupffer cells via NADPH oxidase
and inducible nitric oxide synthase contribute to inflammatory mediator production, via enhanced ROSsensitive
signaling pathways (NF-kB, MAPK, AP-1, Egr1) (Figure 2).
Alcohol-induced autophagy. Autophagy is an intracellular degradation pathway by which lysosomes
degrade proteins and lipids, remove misfolding protein and damaged organelles including mitochondria.
Experimental findings obtained in a model of bindge drinking indicate that alcohol activates autophagy
in hepatocytes, leading to reduction of hepatocyte apoptosis and reduction of fat accumulation (10). The
relevance of this protective effect of autophagy in patients with alcoholic liver disease remains to be clarified.
CONCLUSION
Despite recent advances in the understanding of the molecular mechanisms governing alcoholic liver
disease progression, the development of new therapies is clearly awaited. Novel pathways have been
identified, owing to the use of animal models that only recapitulate the first steps of the disease, i.e fatty
liver, Kupffer cell activation with mild hepatocellular injury. Therefore, there is an urgent need to develop
new animal models with more severe forms of ALD, to further validate the relevance of pathways and
identified targets in more advanced steps of the disease.
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Treatment of alcohol-induced liver disease should ideally reduce steatogenesis, oxidative stress,
inflammation and fibrogenesis, while sparing liver regeneration. In this respect, novel potential therapeutic
targets have been identified, that include i) molecules that will modify gut microbiota (probiotics), neutralize
LPS or antagonize TLR4 (4); ii) compounds targeting CXC chemokines, IL17 or their receptors, because of
their major role in inflammatory cell (neutrophil) infiltration (2, 4, 7); iii) sirtuin activators and iv) molecules
targeting cannabinoid receptors, i.e CB2 agonists and CB1 antagonists, because of their expected
antiinflammatory, antisteatogenic, hepatoprotective and antifibrogenic effects (11, 12). Further translational
research is clearly awaited to evaluate the therapeutic relevance of these newly identified targets.