studies

866A AASLD ABSTRACTS HEPATOLOGY, October, 2015
1334
Inflammatory and apoptotic markers in alcoholic hepatitis
patients: interim analyses
Leila Gobejishvili 1 , Vatsalya Vatsalya 1 , Mohammad K. Mohammad
1 , Shirish Barve 1 , Craig J. McClain 1,2 ; 1 Department of Medicine/GI,
University of Louisville, Louisville, KY; 2 Robley Rex VAMC,
Louisville, KY
This study is part of a NIAAA UO1 consortium to identify novel
biomarkers and unique drug targets for treatments for AH. 17
male and female acute AH patients within the age group of
21-70 yrs. and 10 healthy controls were included in this initial
pilot investigation. Clinical data for demographic, drinking
history and liver injury markers, MELD, Maddrey DF, and CTP
were recorded. Among AH patients, 6 had a MELD score in a
non-severe range (≤ 19) and 11 were in the severe range (≥
20). Milliplex analysis of serum analytes including cytokines,
soluble FasL, Osteopontin (OPN) and TNF-related apoptosis-inducing
ligand (TRAIL) was performed. A major finding of
our study demonstrates significant inverse correlation of TRAIL
expression with severity of AH represented by MELD and neutrophillia.
AH patients often have hepatic polymorphonuclear
leukocyte infiltration and neutrophilia which plays a major role
in determining whether patients develop acute inflammation.
Importantly, resolution of acute inflammation involves neutrophil
apoptosis mediated by TRAIL. In view of this, association
of the decreasing levels of TRAIL with increasing severity of AH
suggests that this could be a significant pathogenic mechanism
that contributes to the development and severity of AH. In comparison,
there was significant direct correlation of sFasL levels
with the severity of AH in our patient population. Fas/FasL
mediated apoptosis plays a major role in hepatocyte death
that occurs in the proinflammatory cytokine milieu of alcoholic
hepatitis. Similar increase in circulating sFasL has been
reported in severe AH patients (Maddrey score ≥32). Further,
as reported previously, AH patients showed significantly higher
serum Osteopontin levels compared to controls and positively
correlated with MELD. Overall, the findings of our initial pilot
study have begun to identify relevant AH-specific pathogenic
determinants that could serve as prognostic biomarkers and
targets for intervention.
Significant inverse correlation between serum TRAIL levels and
MELD in AH patients.
1335
Zinc deficency inactivate hepatic mitochondrial biogensis
pathway in rats chronically fed alcohol: A mechanism
of perturbed hepatic mitochondrial respiratory
complexes and ROS generation
Qian Sun, Wei Zhong, Wenliang Zhang, Zhanxiang Zhou; Nutrition,
University of North Carolina at greensboro, Kannapolis, NC
Clinical studies demonstrated that patients with alcoholic liver
disease (ALD) have a decreased hepatic zinc level, however,
the effect of zinc deficiency on the function of hepatic mitochondria
has not been well studied. The present study was
undertaken to determine if zinc deficiency causes mitochondrial
electron transport chain (ETC) defect and if defected ETC
function could increase hepatic oxidative stress in the presence
of fatty acid and acetaldehyde. Wistar rats were pair-fed with
the Lieber-DeCarli control or ethanol diet for 5 month. Chronic
alcohol exposure significantly increased hepatic triacylglycerol,
free fatty acid and 4-hydroxynonenal (4HNE) levels, meanwhile
hepatic mitochondrial 4HNE level was also increased
and mitochondrial zinc level was reduced. In addition, hepatic
mitochondrial respiratory complex I, III, IV and V were significantly
decreased by chronic alcohol exposure, which was in
consistence with decreased hepatic ATP production. Mitochondrial
biogenesis signal transduction pathway was impaired
by chronic alcohol feeding as indicated by decreased AMPK,
PGC1αa, NRF1 and TFAM levels and mitochondrial DNA
expression. In order to define the link between zinc deficiency
and the defect of mitochondrial respiratory complexes, hepG2
cells were treated with TPEN for 6h. The results indicated that
zinc deficiency significantly decreased mitochondrial respiratory
complex I, III, IV expression. In addition, AMPK, PGC1α,
NRF1 and TFAM levels, and mitochondrial DNA expression
were significantly decreased by TPEN treatment. Consequently,
mitochondrial respiratory complex I, III, IV was silenced by
shRNA, respectively. The transfected hepG2 cells all showed
a decrease in mitochondrial membrane potential and an
increase in free radical production after challenged with 500
mM linoleic acid or 200mM acetaldehyde for 6h. These results
suggest that alcohol exposure induced hepatic zinc deficiency
could inactivate mitochondrial biogenesis signal transduction
pathway and decrease mitochondrial DNA production, which,
in turn, decreases mitochondrial complex protein expression.
The defect of mitochondrial respiratory complexes could
worsen alcohol consumption induced free radical production
while metabolizing fatty acid and acetaldehyde.
Disclosures:
The following authors have nothing to disclose: Qian Sun, Wei Zhong, Wenliang
Zhang, Zhanxiang Zhou
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: Leila Gobejishvili, Vatsalya Vatsalya,
Mohammad K. Mohammad
1336
Nuclear receptor Rev-Erbα functions as a transcriptional
activator of Chop to control SHP mediated alcoholic
fatty liver
zhihong yang 1 , Hiroyuki Tsuchiya 2 , Sangmin Lee 1 , Yuxia Zhang 3 ,
Li Wang 1 ; 1 PNB, university of Connecticut, Hamden, CT; 2 School
of Medicine, university of Utah, Salt Lake City, UT; 3 Pharmacology,
Toxicology & Therapeutics, University of Kansas Medical Center,
Kansas City, KS
[Purpose] Excessive consumption of alcohol results in development
steatosis and steatohepatitis, which can progress to
cirrhosis and hepatocellular carcinoma. The endoplasmic reticulum
(ER) stress contributes to metabolic disturbances and is
associated with alcoholic liver disease (ALD). This project aims
at identifying new molecular mechanisms in nuclear receptor