studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 867A
mediated circadian regulation of alcoholic fatty liver. [Methods]
The ethanol-binge model (NIAAA model) used in the
current study is described previously. Briefly, two months old
C57BL/6 (WT) and nuclear receptor Shp-/- mice were fed
with Lieber-DeCarli diet containing 5% ethanol ad libitum or
pair- fed with the isocaloric control diet for 10 days. On day
11, mice were oral-gavaged with a single dose of 5g of ethanol/kg
of body weight (EtOH) or maltose dextrin (CTRL). After
nine hours, the serum and liver samples were collected every
six hours for twenty-four hours, subjected to mRNA analysis by
qPCR and RNA-seq or protein expression analysis by Western
Blotting. [Results] Liver TG levels, lipid accumulation and glycogen
increased significantly in WT mice after ethanol binge
compared to control group fed isocaloric diet, but decreased
in Shp -/- mice. Surprisingly, Shp-/- mice receiving control diet
exhibited higher basal levels of TG and lipid accumulation.
Srebp1c mRNA and protein expression were also elevated
in Shp -/- mice, but were reduced in EtOH group, as well as
Fasn, one of Srebp1c’s targets. ER stress markers p-eIf2a and
Atf4 protein increased due to alcohol treatment in WT mice
and the increase is abrogated in Shp-/- mice. The transcription
factor C/EBP homologous protein (Chop) is an evidenced
downstream target of ATF4. Unexpectedly, the basal Chop
expression was higher in Shp-/- mice receiving control diet,
Chop was decreased following alcohol binge in both WT and
Shp-/- mice and the expression was in a circadian fashion.
Rev-Erbα functions as a negative-regulator of several clock proteins.
Interestingly, its levels exhibited a similar changes as
Chop. We further demonstrated that Rev-Erbα activated Chop
promoter activity and induced Chop mRNA and protein expression,
which was inhibited by co-expression of Shp. In addition,
knockdown Rev-Erbα by shRNA reduced Srebp1c protein
cleavage. [Conclusions] Our study identified a novel function
of Rev-Erbα to modulate SHP mediated Chop expression and
Srebp1c cleavage, thus providing a new regulatory mechanism
in circadian clock control of alcoholic fatty liver.
Disclosures:
The following authors have nothing to disclose: zhihong yang, Hiroyuki Tsuchiya,
Sangmin Lee, Yuxia Zhang, Li Wang
1337
The Alcoholic Hepatitis Histology Score Performs Poorly
in a Cohort of Severe Alcoholic Hepatitis in the United
States
Gene Y. Im 1 , Aparna Goel 1 , Stephen C. Ward 2 , Yujin Hoshida 1 ,
Thomas D. Schiano 1 , Scott L. Friedman 1 , Swan N. Thung 2 ; 1 Medicine,
Division of Liver Diseases, Icahn School of Medicine at Mount
Sinai, New York, NY; 2 Pathology, Icahn School of Medicine, New
York, NY
Prediction models for alcoholic hepatitis (AH) that are commonly
used only include clinical variables. The Alcoholic Hepatitis
Histology Score (AHHS) is a newly derived and validated
histologic prediction model. Our aim was to evaluate the performance
of the AHHS in a real-world cohort of severe AH
patients in the United States. Methods: Patients hospitalized
at a high volume liver transplantation (LT) center for severe
AH were prospectively identified from 1/2012 to 6/2015 for
our AH database. Patients with severe AH on liver histology
obtained early in their hospitalization and with a Maddrey’s
discriminant function (DF) ≥32 were included. Liver histology
slides were reviewed by expert hepatobiliary pathologists
who were blinded to patient characteristics. Clinical data
were reviewed to calculate DF, Lille, model for end-stage liver
disease (MELD), Glasgow alcoholic hepatitis score (GAHS)
and age, bilirubin, INR, creatinine (ABIC) scores at presentation.
The primary outcome of analysis was 90-day mortality or
LT. Results: Over the 3.5 year study period, 120 consecutive
patients with severe AH were admitted or transferred to our
liver service and prospectively evaluated. Twenty-six patients
had available liver tissue for analysis. The median age was 44
years (IQR 38-53) and two-thirds Caucasian with female predominance.
Median DF, MELD, Lille, GAHS and ABIC scores
were 78 (IQR 58-93), 33 (IQR 26-39), 0.970 (IQR 0.41-
0.99), 7.5 (7-9) and 8.9 (7.8-9.7), respectively, indicative of
a cohort with high risk of mortality. Standard medical care for
advanced liver disease was provided, with less than one-quarter
receiving glucocorticoid-based therapies and half ineligible
due to severe illness. The cumulative mortality or LT rates at
day 30, 60, 90 and 180 were 42%, 46%, 65% and 69%,
respectively. The AHHS model performed poorly in predicting
90-day mortality or LT, with an area under the curve (AUC) of
0.57. The Lille and GAHS models performed well with AUCs
of 0.83 and 0.71, respectively, while MELD and ABIC had
AUCs of 0.56 and 0.55, respectively. Conclusions: The AHHS
model performed poorly in predicting 90-day mortality or LT in
a real-world cohort of severe AH patients in the United States.
As a static histologic score, the AHHS may lack the precision to
capture the dynamic clinical complexity of severe AH.
Disclosures:
Thomas D. Schiano - Advisory Committees or Review Panels: salix, merck, gilead,
pfizer; Grant/Research Support: galectin, massbiologics, biotest
Scott L. Friedman - Advisory Committees or Review Panels: Pfizer Pharmaceutical;
Consulting: Conatus Pharm, Exalenz, Genfit, Exalenz Biosciences, Eli Lilly PHarmaceuticals,
Fibrogen, Boehringer Ingelheim, Nitto Corp., Immune Therapeutics,
Synageva, Roche/Genentech Pharmaceuticals, DeuteRx, Abbvie, Novartis,
RuiYi, Kinemed, Sanofi Aventis, Takeda Pharmaceuticals, Nimbus Therapeutics,
Bristol Myers Squibb, Astra Zeneca, Sandhill Medical Devices, Galmed, Northern
Biologics, Enanta Pharmaceuticals, Regado Bioscience, Raptor Pharmaceuticals,
Teva Pharmaceuticals, Zafgen Pharmaceuticals, Merck Pharmaceuticals,
Debio Pharmaceuticals; Grant/Research Support: Galectin Therapeutics, Tobira
Pharm; Stock Shareholder: Angion Biomedica, Intercept Pharma
The following authors have nothing to disclose: Gene Y. Im, Aparna Goel, Stephen
C. Ward, Yujin Hoshida, Swan N. Thung
1338
Genetic Ablation of MitoNEET Alleviates Alcoholic Steatosis/Steahepatitis
in Mice
Alvin Jogasuria 1 , Werner J. Geldenhuys 1 , Jiayou Wang 1,2 , Xudong
Hu 1,3 , Kwangwon Lee 1 , Prabodh Sadana 1 , Jiashin Wu 1 ,
Min You 1 ; 1 Pharmaceutical Sciences, Northeast Ohio Medical
University (NEOMED), Rootstown, OH; 2 Department of Anatomy,
Guangzhou University of Chinese Medicine, Guangzhou, China;
3 Department of Biology, Shanghai University of Traditional Chinese
Medicine, Shanghai, China
MitoNEET (CDGSH iron-sulfur domain-containing protein 1
or CISD1) is an outer mitochondrial membrane protein that
donates 2Fe-2S clusters to apo-acceptor proteins, and regulates
mitochondrial matrix iron metabolism. Clinically, aberrant
hepatic iron metabolism is frequently occurred in patients
with alcoholic liver disease. It is also reported that, in vitro
cultured hepatocytes, ethanol along with fructose induces a
large increase in the expression of mitoNEET, which primed the
fructose and ethanol exposed hepatocytes for TNFα-induced
necroptosis. Therefore, in the present study, using a mitoNEET
knock out (MitoNEETKO) mouse model, we aimed to investigate
the in vivo functional role of mitoNEET in the development
of alcoholic steatosis/steatohepatitis and explore the underlying
mechanisms. Alcoholic fatty liver injury was achieved
by pair feeding wild-type (WT) and MitoNEETKO mice with
Lieber-DeCarli ethanol-containing diets for 4-wks. Remarkably,
we found that chronically ethanol-fed MitoNEETKO mice were
resistant to ethanol-induced fatty liver injury demonstrating by