studies

268A AASLD ABSTRACTS HEPATOLOGY, October, 2015
ing significant reduction in certain long- (hexadecanoic and
heptadecanoic), medium (hexanoic and octanoic), and short
(butanoic) free fatty acids. Remarkably, the levels of octanoic
acid (known to have antimicrobial properties) were dramatically
reduced (~48 fold) in mice fed USF+EtOH compared to
SF+EtOH fed animals. A decline in certain fecal amino acids
(e.g. serine and glycine) was observed in USF+EtOH fed animals.
Conclusions: These data support an important role of
dietary lipids in ALD pathogenesis, and provide insight into
mechanisms of ALD development. A diet enriched in USF not
only enhanced alcohol-induced liver injury, but also caused
major fecal metagenomic and metabolomic changes that may
play an etiologic role in observed liver injury. Characterization
of both microbiota composition and function is an important
approach to investigate host–microbial interaction. Our data
suggest that dietary lipids can potentially serve as interventions
for the prevention/treatment of ALD.
Disclosures:
Shirish Barve - Speaking and Teaching: Abbott
Craig J. McClain - Consulting: Vertex, Gilead, Baxter, Celgene, Nestle, Danisco,
Abbott, Genentech; Grant/Research Support: Ocera, Merck, Glaxo SmithKline;
Speaking and Teaching: Roche
The following authors have nothing to disclose: Irina Kirpich, Wenke Feng, Xinmin
Yin, Xiaoli Wei, Xiang Zhang
115
PEGylated TRAIL treatment ameliorates liver cirrhosis in
rats by targeting activated hepatic stellate cells
Ogyi Park 1,2 , Yumin Oh 1,2 , Magdalena Swierczewska 1,2 , Jong
Sung Park 1,2 , Justin Hanes 2 , Martin Pomper 1 , Bin Gao 3 , Seulki
Lee 1,2 ; 1 The Russell H. Morgan Department of Radiology and
Radiological Sciences, Johns Hopkins University, Baltimore, MD;
2 The Center for Nanomedicine at the Wilmer Eye Institute, Johns
Hopkins University School of Medicine, Baltimore, MD; 3 Laboratory
of Liver Diseases, National Institute of Alcohol Abuse and
Alcoholism, National Institutes of Health, Bethesda, MD
Background: Liver fibrosis is a common outcome of chronic
liver disease and leads to liver failure and cancer. Still, no targeted
anti-fibrotic therapy exists at this time. Activated hepatic
stellate cells (aHSCs) are the originators of liver fibrosis; therefore,
eradication of aHSCs is a logical strategy to stop and/
or reverse liver fibrosis. However, there are no effective strategies
to specifically deplete apoptosis-resistant aHSCs during
fibrosis without systemic toxicity. TRAIL is known to selectively
induce apoptosis in cancer cells or transformed cells by binding
to its death receptors (DRs) while sparing normal tissue.
But because recombinant TRAIL suffers from a short half-life
and low potency, it failed to show efficacy in cancer clinical
trials. Here we introduce a longer-acting, more stable form
of TRAIL that shows striking anti-fibrotic activity in rat fibrosis
and cirrhosis models with no detected hepatotoxicity. Methods:
We developed PEGylated TRAIL (TRAIL PEG
) by stabilizing a
potent homotrimer TRAIL of iLZ-TRAIL with a 5kDa PEG. In in
vivo studies, SD rats were induced liver fibrosis and cirrhosis
by CCl 4
and treated with 4 mg/kg of TRAIL PEG
daily for 10
days for fibrosis and two weeks for cirrhosis. In in vitro studies,
primary human HSCs were culture-activated and TRAIL PEG
effects were investigated on quiescent and activated HSCs.
Primary human hepatocytes were used to determine hepatotoxicity
of TRAIL PEG
. Results: Intravenously injected TRAIL PEG
has a markedly extended half-life in non-human primates and
no toxicity in primary human hepatocytes. We found DRs are
upregulated in human cirrhotic livers because of aHSCs. In
vitro primary human aHSCs, but not quiescent HSCs, become
sensitive to TRAIL PEG
-induced apoptosis via DR- and DISC-activated
caspase-8-dependent mechanisms. Intravenous TRAIL PEG
directly induced apoptosis of aHSCs and ameliorated CCl 4
-induced
fibrosis/cirrhosis in rats by simultaneously down-regulating
multiple key fibrogenic molecules in vivo. TRAIL PEG
also
caused selective toxicity to hepatocellular carcinoma (HCC)
cells. Conclusions: TRAIL-based therapies could serve as firstin-class
therapeutics for liver fibrosis/cirrhosis, cirrhosis-associated
HCC and possibly other fibrotic diseases. Our results not
only introduce the unique activity that TRAIL-based compounds
have in liver fibrosis but also warrant clinical translation of
TRAIL PEG
for severe liver fibrosis therapy.
Disclosures:
The following authors have nothing to disclose: Ogyi Park, Yumin Oh, Magdalena
Swierczewska, Jong Sung Park, Justin Hanes, Martin Pomper, Bin Gao,
Seulki Lee
116
Statins, ACE inhibitors and ARB use is associated with
reduced mortality and morbidity in chronic liver diseases
– a nationwide cohort study in Sweden
Knut Stokkeland 1,2 , Christine Takami Lageborn 3 , Anders Ekbom 4 ,
Jonas Höijer 5 , Matteo Bottai 5 , Per Stål 6 , Karin Söderberg Löfdal 7 ;
1 Department of Medicine, Visby Hospital, Visby, Sweden; 2 Karolinska
Institutet, Department of Medicine, Gastroenterology and
Hepatology, Stockholm, Sweden; 3 Karolinska Institutet, Stockholm,
Sweden; 4 Department of Medical Epidemiology and Biostatistics,
Karolinska Institutet, Stockholm, Sweden; 5 Unit of Biostatistics,
IMM, Karolinska Institutet, Stockholm, Sweden; 6 Division of Hepatology,
Karolinska Hospital, Stockholm, Sweden; 7 Division of Clinical
Pharmacology, Department of Laboratory Medicine, Karolinska
Institutet, Stockholm, Sweden
Aim: To explore whether current medication in patients with
chronic liver diseases affect overall mortality, liver-related mortality
and liver-related morbidity. Methods: We performed a
register-based cohort study in Sweden with patients with a
first-time diagnosis of chronic liver disease between 2005 and
2012. We studied the use of statins, angiotensin converting
enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB),
acetylsalicylic acid (ASA), non-steroidal anti-inflammatory
drugs (NSAID), selective seretonin re-uptake inhibitors (SSRI)
and antibiotics. We measured total mortality, liver-specific
mortality and liver-specific morbidity. We used register data
from the Patient Register, the Prescribed Drug Register and the
Death Certificate Register. Liver-specific morbidity and mortality
included all liver diseases, esophageal varices and liver
cancer. Results: We analyzed 70 546 patients who had been
seen in hospital out-patient services or hospitalized with chronic
liver disease for the first time between 2005 and 2012. We
found a reduction in mortality risk for statin users (n= 8 688)
with a hazard ratio range between 0.42 (95% CI: 0.28-0.63)
for patients with autoimmune hepatitis and 0.91 (0.63-1.32)
for primary biliary cirrhosis with a similar risk reduction for
liver-specific mortality and liver-related morbidity. There was
a significant mortality reduction for patients exposed to ARB
(n= 6204) between 0.62 (0.53-0.72) in alcoholic liver disease
and 0.91 (0.64-1.32) in primary biliary cirrhosis and a similar
reduction for patients exposed to ACEi (n=9 714). There was
a significant reduction of liver morbidity in patients exposed to
ASA (n= 9 768) for all chronic liver diseases, even among users
of NSAID (n= 14 119). An increased risk for all-cause mortality
was seen for almost all liver diseases in patients exposed to
SSRI (n= 11 048), with a range between 1.25 (1.16-1.35) and
1.61 (1.30-1.98), and a reduction in risk of liver-specific morbidity
for almost all diagnoses. There was a reduction in risk for
liver morbidity for patients exposed to antibiotics (n= 27 756)
between 0.55 (0.44-0.70) and 0.77 (0.73-0.80). Conclusion: