studies

872A AASLD ABSTRACTS HEPATOLOGY, October, 2015
tive diets for 4-5 weeks. At the end of the feeding regimen, the
rats were sacrificed and blood, livers and relevant extrahepatic
tissues were collected and processed for biochemical and histological
analyses. We observed micro- and macro-vesicular
steatosis and a 4 fold-increased triglyceride accumulation in
the livers of rats fed the ethanol diet compared to the controls.
Creatine supplementation neither prevented alcoholic
steatosis nor decreased elevated plasma ALT levels. The lower
hepatocellular SAM:SAH ratio seen in the ethanol-fed rats was
also not normalized when these rats were fed the creatine
supplemented ethanol diet nor were SAM levels increased in
these rats. However, a >10-fold increased level of creatine
was observed in the liver, serum, muscles and hearts of rats fed
the creatine-supplemented control and ethanol diet. Overall,
dietary creatine supplementation did not prevent alcoholic liver
injury despite its known efficacy in preventing high-fat diet-induced
steatosis. To conclude, creatine is ineffective in protecting
against the development of alcoholic steatosis. Betaine, a
pro-methylating agent that maintains hepatocellular SAM:SAH
and prevents alcoholic steatosis still remains our best option for
this treatment.
Disclosures:
The following authors have nothing to disclose: Dan Feng, Ryan W. Barton, Paul
G. Thomes, Dean J. Tuma, Natalia A. Osna, Kusum K. Kharbanda
1348
The L-carnitine alleviate hepatic fibrosis in a non-alcoholic
steatohepatitis
Hajime Sunagozaka 1 , Masao Honda 1 , Taro Yamashita 1 , Hikari
Okada 1 , Naoki Oishi 1 , Tetsuro Shimakami 1 , Kazuya Kitamura 1 ,
Kuniaki Arai 1 , Yoshio Sakai 1 , Tatsuya Yamashita 1 , Naoto
Nagata 2 , Toshinari Takamura 2 , Eishiro Mizukoshi 1 , Shuichi
Kaneko 1 ; 1 Department of gastroenterology, kanazawa university
Hospital, Kanazawa, Japan; 2 Department of Disease Control and
Homeostasis, Kanazawa University Graduate School of Medical
Sciences, kanazawa Ishikawa, Japan
BACKGROUND & AIMS Non-alcoholic steatohepatitis (NASH)
is a known metabolic disorder of the liver. No treatment has
been conclusively shown conclusively to improve NASH or
prevent disease progression. The function of L-carnitine to
modulates the lipid profile, oxidative stress, and inflammatory
responses. In this study, we evaluated the efficacy of L-carnitine
for the prevention of NASH. METHODS Eight-week-old male
C57BL/6J mice were divided into four groups: (1) basal diet,
(2) atherogenic high-fat (Ath+HF) diet, (3) Ath+HF+0.5% carnitine
diet, and (4) Ath+HF+1% carnitine diet. Liver histology
and gene expression profiles were evaluated at base line and
after 12, 30weeks of L-carnitine administration. Furthermore,
in the clinical research, we administered 1800 mg L-carnitine
for 24 weeks to the patients who have beenwere diagnosed
histologically with histologically NASH for 24 weeks.
We evaluated liver enzymes, lipid and glucose profiles, and
histological scores at the start and end of treatment. Gene and
protein expression were was evaluated by qRT-PCR and western
blotting, respectively. Metabolome analysis was performed
with mice mouse and Hhuman liver tissue samples to detect the
changes of in metabolic path ways with induced by L-carnitine
administration. RESULTS the L-carnitine significantly decreased
liver weight and triglyceride TG and total cholesterol TC levels
compared with the Ath+HF groups in a dose- dependent
manner. Furthermore, the L-carnitine, as compared with the
Ath+ & HF group, was associated with significant reductions
in hepatic steatosis, lobular inflammation, and fibrosis score
at 12 and 30 weeks in a dose- dependent manner. qRT-PCR
analysis demonstrated that L-carnitine significantly reduced
the alteredation of expression of the pro-fibrotic, inflammatory,
and fat synthesis-associated genes, whereas the expression
of PPAR-alpha expression was significantly increased. In
Human researchthe NASH patients, L-carnitine -treated patients
showedadministration significantly improvedments in the liver
enzymes, and histological scores at the end of the treatment
period. In metabolome analysis, the pentose phosphate pathway
was accelerated with L-carnitine, whereas the glycolysis
pathway was not activated directlyory. In this pathway, a
large amount of NADPH was produced and the glutathione
redox ratio was increased in the liver tissue. CONCLUSIONS
L-carnitine supplementation improved hepatic steatosis, inflammation,
fibrosis. L-carnitine could reduce an oxidativeon stress
through the modification of the pentose phosphate pathway
in the NASH liver. L-carnitine could be serve as a candidate
therapeutic strategy for NASH.
Disclosures:
Hikari Okada - Employment: Kanazawa University
Shuichi Kaneko - Grant/Research Support: MDS, Co., Inc, Chugai Pharma., Co.,
Inc, Toray Co., Inc, Daiichi Sankyo., Co., Inc, Dainippon Sumitomo, Co., Inc,
Ajinomoto Co., Inc, Bristol Myers Squibb., Inc, Pfizer., Co., Inc, Astellas., Inc,
Takeda., Co., Inc, Otsuka„ÄÄPharmaceutical, Co., Inc, Eizai Co., Inc, Bayer
Japan, Eli lilly Japan
The following authors have nothing to disclose: Hajime Sunagozaka, Masao
Honda, Taro Yamashita, Naoki Oishi, Tetsuro Shimakami, Kazuya Kitamura,
Kuniaki Arai, Yoshio Sakai, Tatsuya Yamashita, Naoto Nagata, Toshinari
Takamura, Eishiro Mizukoshi
1349
Functional role of the Lin28/let-7 system during alcoholic
liver injury
Kelly McDaniel 2,1 , Tami Annable 2,1 , Yuyan Han 3,2 , Tianhao
Zhou 3,2 , Julie Venter 3,2 , Ying Wan 1,2 , Jessica S. Garner 1 , Nan
Wu 3,2 , Shannon S. Glaser 3,2 , Heather L. Francis 1,2 , Gianfranco
Alpini 3,2 , Fanyin Meng 1,2 ; 1 Scott & White Hospital, Texas A&M
HSC College of Medicine, Temple, TX; 2 Central Texas Veterans
Healthcare System, Temple, TX; 3 Texas A&M HSC College of Medicine,
Temple, TX
Background: Alcoholic liver disease (ALD) is a serious health
concern affecting millions of patients each year. Progression of
alcoholic liver disease (ALD) involves steatosis, inflammation
and subsequent fibrosis leading to cirrhosis of the liver. microR-
NAs including let-7 family have the therapeutic potentials to
recover the liver injury and fibrosis. Lin28 has been shown
to bind to the let-7 pre-microRNA and subsequently block the
maturation of let-7. Our aim is to evaluate the role of lin28/
let-7 system in alcoholic-induced fibrotic liver disease. Methods:
Lin28a conditional mutant mice (Lin28a tm1.2Gqda/J ) and WT
controls underwent chronic and binge ethanol feeding (NIAAA
model). RNA was extracted from whole liver and analyzed
via PCR array and qPCR for fibrosis markers and microRNA.
PCR array data was further analyzed with the GO Enrichment
Analysis tool. Serum from mice was analyzed via ELISA for
TGF-beta levels. Immunohistochemistry (IHC) was performed
on liver sections for fibrosis markers and morphological analysis.
Results: The total liver histopathology score significantly
increased in ethanol WT group relative to control WT mice,
and decreased in Lin28 mutant group relative to WT control
mice with ethanol treatment. By PCR array, ethanol treated
Lin28a mutant mice showed increase in genes associated with
low-density lipoprotein particle receptor, inflammation, vitamin
D synthesis and calidiol 1-monooxygenase activity compared
to Lin28a mutant mice. Lin28a mutant mice treated with ethanol
also showed a decrease in genes associated with primary
miRNA processing and foregut morphogenesis compared to
Lin28a mutant mice. Compared to wild type animals treated
with ethanol, Lin28a mutant mice treated with ethanol showed