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

BARCELONA . SPAIN
46 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 47
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
in order to resolve or restrict the possible cellular damage. In patients with ALD, cellular stress is severe
and persistent, leading to hepatic cellular death (lipo-apoptosis) and necrosis by induction of the c-Jun
N-terminal Kinase (JNK) signaling pathway. This process of persistent ethanol-induced hepatic injury is
not restricted to hepatocytes, as many studies suggest the existence of a relevant crosstalk with other
hepatic cell types. Indeed, ethanol-induced oxidative stress is also present in activated Kupffer cells, which
are responsible for the secretion of pro-inflammatory cytokines, linking alcohol abuse to inflammation.
Hepatic stellate cells (HSC) are activated in a paracrine manner by acetaldehyde and ROS produced by
the metabolism of ethanol in the surrounding hepatocytes and Kupffer cells. ROS-dependent activation of
HSC, upon ethanol-induced hepatocyte damage, leads to deposition of collagen and other extracellular
matrix components. As a consequence, perivenular and periportal fibrosis is established, eventually leading
to bridging fibrosis and cirrhosis. These changes are typical features of alcoholic fibrosis and often coexist
with the findings of ASH.
Chronic ethanol abuse decreases NK cell activity. NK cells are thought to participate in the killing of HSC
after their activation, thus providing a mechanism for the limitation of fibrosis. In contrast, NK T-cells are
activated early in the response to ethanol feeding. With respect to fibrosis, activation of NKT has been
reported to have pro- or antifibrogenic actions, and their role in ALD-associated fibrosis needs to be further
elucidated.
MECHANISMS OF FIBROGENESIS COMMON TO ASH AND OTHER LIVER DISEASES, INCLUDING NASH
Alcoholic and nonalcoholic steatohepatitis (NASH) have similar histological features and spectrum of
disease. Therefore, it is not surprising that recent research has identified mechanisms that are in common
between these two conditions. In addition, some fibrogenic mechanisms are operating also in the progression
of other forms of chronic liver diseases.
Apoptosis. ASH and other forms of liver injury are characterized by hepatocyte apoptosis, and generation
of apoptotic bodies has been recognized as a potent profibrogenic stimulus.
Endogenous cannabinoid system. Cannabinoids are a group of molecules with modulatory properties on
liver fibrogenesis. HSCs express both cannabinoid receptors and inactivation of CB1 receptors decreases
fibrogenesis by lowering hepatic TGF-β1 and reducing the accumulation of fibrogenic cells in the liver.
The role of cannabinoids derived by HSC has also been implicated in the pathogenesis of alcohol induced
steatosis. While rimonabant, the first CB1 antagonist to enter clinical practice, has been recently withdrawn
from the market due to psychiatric side effects, a new generation of antagonists that do not cross the bloodbrain
barrier are promising for the treatement of fibrogenic disorders. On the other hand, CB2 activation
provides antifibrogenic signals.
CONCLUSIONS AND PERSPECTIVES
Fibrosis in ALD has peculiarities that differentiate it from the one that is observed in other forms of liver
disease, both from the pathological point of view and for the molecular mechanisms that characterize it.
Nonetheless, some mechanisms are in common, particularly with nonalcoholic steatohepatitis but also with
other forms of fibrogenesis. Application of translational research, which combines studies in humans with
mechanistic information from preclinical investigation is the challenge for the discovery of new therapeutic
targets in the near future.
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Figure 1
Basic features of activated stellate cells. Activation of stellate cells to myofibroblasts is associated with
acquisition of phenotypic changes that make them more suitable to coordinate the wound healing response
and fibrogenesis. Mediators implicated are indicated on the right.
Imbalanced adipokine expression: Recent studies have highlighted a relation between adipokines and
several aspects of ALD, including fibrosis. Data have been obtained particularly for leptin and adiponectin.
Leptin has been shown to mediate profibrogenic effects on the liver. Hepatic stellate cells express functional
leptin receptors and are directly responsive to leptin with a number of biological actions that collectively
promote fibrogenesis. Besides an action on HSC, leptin also targets Kupffer cells and sinusoidal endothelial
cells stimulating TGF-β expression.
Adiponectin increases insulin sensitivity and provides anti-inflammatory signals. A direct antifibrogenic
action of adiponectin has been demonstrated in animals undergoing toxic liver damage and adiponectin
ameliorates liver damage in different models of steatohepatitis. Some of the anti-fibrogenic effects of
adiponectin are dependent on activation of AMP-activated protein kinase, that is activated in hepatic
stellate cells upon interaction of adiponectin with its cognate ligands. Along these lines, adiponectin has
been shown to reduce hepatic damage and fibrogenesis in models of alcoholic liver disease, providing a
molecular counterpart for the observed detrimental effect of obesity on the course of ALD.