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

BARCELONA . SPAIN
148 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 149
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
Recently translational studies of human liver samples and animal models have identified several novel
therapeutic targets.1, 2 These include targets that can be used to block liver inflammation in ALD, and
targets that can be used to promote hepatocyte survival and proliferation.
Figure 2 summarizes the STAT3 signaling activated by various cytokines in hepatocytes.
THE TARGETS THAT CAN BE USED TO BLOCK LIVER INFLAMMATION IN ALD:
CXC chemokines:
The CXC family of chemokines includes IL-8 and Gro-α; these usually attract neutrophils, which infiltrate
livers of patients with ALD. In patients with AH, hepatic expression of CXC chemokines is increased and
correlates with survival time and the degree of portal hypertension. Reagents that target CXC chemokines
might be developed as therapeutics for AH.
Gut microbiota and LPS pathway:
Modulation of the gut microbiota and LPS pathways might also be used to treat patients with ALD. The
gut microbiota and LPS signaling can be modified by probiotics and TLR4 antagonists, respectively, with
the latter being proposed as therapeutic agents for the treatment of chronic liver diseases, including ALD.
Results from a placebo-controlled trial recently showed that the nonabsorbable antibiotic rifaximin, which
modifies the gut microbiota, protected patients from hepatic encephalopathy. Reagents that alter the gut
microbiota might also prevent ALD, so further studies are required.
Complement:
Activation of complement is an important step in the development of ethanol-induced liver injury in mice.
Therapeutic interventions to either block complement activation or increase the activity of negative regulators
of complement might be used to treat patients with ALD. Several compounds that inhibit complement
activation are in phase 1 or 2 trials for the treatment of age-related macular degeneration. These drugs
may be developed to treat patients with ALD.
Osteopontin:
Osteopontin is an extracellular matrix protein that is markedly up-regulated in patients with ALD. The
basal expression levels of osteopontin correlate with disease severity (R. Bataller et al, unpublished
data, September 2011), indicating that osteopontin contributes to the pathogenesis of ALD. Blockade of
osteopontin might be effective for amelioration of ALD.
THE TARGETS THAT CAN BE USED TO PROMOTE HEPATOCYTE SURVIVAL AND PROLIFERATION
IN ALD:
Apoptosis inhibitors:
Apoptosis is a prominent feature of chronic liver disease, so apoptosis inhibitors have been investigated
in animal models of liver injury and patients with chronic liver diseases. Multiple clinical trials have shown
that various caspase inhibitors reduced liver injury and fibrosis in patients with chronic HCV infection or
nonalcoholic steatohepatitis.156 ALD is also associated with significant levels of hepatocyte apoptosis, so
inhibitors might be a treatment option for ALD.
Interleukin-22 (IL-22):
IL-22 is a recently discovered hepatoprotective cytokine and seems to have many beneficial effects for the
treatment of ALD. IL-22 was originally identified as an IL-9-induced gene and belongs to IL-10 family, but
IL-22 and IL-10 have very different biological functions. In contrast, IL-22 has very similar hepatoprotective
functions as IL-6 via the activation of signal transducer and activator of transcription 3 (STAT3) in hepatocytes.
Figure 2: STAT3 signaling in hepatocytes. Hepatocytes express high levels of gp130, which is a common
signal chain for IL-6 and IL-6 family cytokines, high levels of IL-6 receptors and various corresponding
receptors for IL-6 family cytokines. IL-6 family cytokines include leukemia inhibitory factor (LIF), ciliary
neurotrophic factor (CNTF), oncostatin M (OSM), cardiotrophin-1 (CT-1), and IL-11. The ligation of these
cytokines (IL-6 and IL-6 family cytokines) with their corresponding receptors leads to the dimerization of
gp130, followed by dimerization of gp130-associated Janus kinases (JAKs) and phosphorylation of JAKs
and gp130. This receptor-kinase complex then recruits and phosphorylates cytoplasmic protein STAT3.
Phosphorylated STAT3 forms a dimer, translocates into the nuclei and subsequently induces transcription
of many genes. Hepatocytes also express high levels of IL-22R1 and IL-10R2 for IL-22 signaling. IL-6, IL-6
family cytokines, and IL-22 predominantly activate STAT3, but also induce a weak activation of other STATs
and MAP kinases. Human hepatocytes express high levels of IFNAR1 and functional IFNAR2c. IFN-α/β
predominately induces STAT1 activation in primary human hepatocytes but also induces strong STAT3
activation. Activated STAT3 induces transcription of many genes that play important roles in inducing acute
phase responses, promoting hepatocyte survival and liver regeneration, and ameliorating fatty liver. (Wang
H., Lafdil F., Kong, X., and Gao, B.: International Journal of Biological Sciences 2011,7:536-550)
In 2004, we demonstrated for the first time that IL-22 is a critical survival factor for hepatocytes and plays
a key role in protecting against Con A-induced T cell hepatitis.3 The hepatoprotetion of IL-22 in T cell
hepatitis was further confirmed using IL-22-deficient mice 4 and IL-22 transgenic mice.5 In addition, IL-22
ameliorates steatosis and hepatocellular damage in many other models of liver injury, including high fat
diet-induced fatty liver 6 and acute and chronic alcoholic liver injury.7, 8 The hepatoprotective effect of
IL-22 in alcoholic liver injury is likely mediated via the activation of STAT3, followed by the upregulation of
anti-apoptotic genes (e.g., Bcl-2 and BcI-xL), anti-oxidative genes (e.g., metallothioneins 1 and 2), and the
downregulation of lipogenic genes (e.g., SREBP-1c) in hepatocytes (Fig. 3).