studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 673A
which in turn lead to activation of CaMKII and AMPK. These
findings identify a likely mechanism by which Them2 promotes
hepatic glucose production in response to high fat feeding and
provide a rationale for targeting Them2 in the management of
NAFLD.
Disclosures:
David E. Cohen - Advisory Committees or Review Panels: Merck, Aegerion,
Genzyme; Consulting: Intercept
The following authors have nothing to disclose: Baran A. Ersoy, Yingxia Li
943
Genetic analysis of NAFLD within a Caribbean Hispanic
Population
Devorah Edelman 2 , Bernice Morrow 2 , Maria Delio 2 , Mortadha
Abd 4 , Adam Auton 2 , Tao Wang 3 , Allan W. Wolkoff 1,4 , Harmit S.
Kalia 1,4 ; 1 Medicine, Albert Einstein College of Medicine, Bronx,
NY; 2 Genetics, Albert Einstein College of Medicine, Bronx, NY;
3 Epidemiology, Albert Einstein College of Medicine, Bronx, NY;
4 Gastroenterology & Liver Diseases, Montefiore Medical Center,
Bronx, NY
We performed the first genetic investigation of Non-alcoholic
fatty liver disease (NAFLD) in Hispanic patients of majority
Caribbean descent. A total of 316 individuals including 40
subjects with biopsy-proven NAFLD, 24 ethnically matched
non-NAFLD controls, and a 252 ethnically-mixed random sampling
of Bronx County, New York were analyzed. Genotype
analysis was performed to determine allelic frequencies of 234
known single nucleotide polymorphisms (SNPs) associated with
NAFLD risk based on previous genome-wide association study
(GWAS) and candidate-gene studies. Additionally, the entire
coding region of PNPLA3, a gene showing the strongest association
to NAFLD was subjected to Sanger sequencing to identify
all exonic variants in our NAFLD samples and controls. The
highly NAFLD-correlated rs738409 polymorphism in PNPLA3
occurred more frequently in the case population than controls
(OR 2.95, p=0.003), the general population (OR 1.97,
p=0.0001), and would be expected in a random Puerto Rican
population (OR 1.56, p= 0.05) based on data from the 1000
Genomes Project. Results suggest that both rare and common
DNA variations in PNPLA3 and SAMM50 may be correlated
with NAFLD in this small population study, while common DNA
variations in CHUK and ERLIN1, may have a protective interaction.
Common SNPs in ENPP1 and ABCC2 have suggestive
association with fatty liver, but with less compelling significance.
In conclusion, Hispanic patients of Caribbean ancestry
may have different interactions with NAFLD genetic modifiers;
therefore, further investigation with a larger sample size, into
this Caribbean Hispanic population is warranted.
Genotyping Results
Disclosures:
Allan W. Wolkoff - Consulting: Synageva; Grant/Research Support: Merck
The following authors have nothing to disclose: Devorah Edelman, Bernice Morrow,
Maria Delio, Mortadha Abd, Adam Auton, Tao Wang, Harmit S. Kalia
944
Inhibitor Of DNA Binding 2 Gene Induced By High Levels
Of Insulin Contributes To Adipogenesis And Fatty
Liver In A Model Of Type 2 Diabetes Mellitus
Tomoyuki Nemoto, Hidetaka Matsuda, Katsushi Hiramatsu, Yoshihiko
Ozaki, Tatsushi Naito, Kazuto Takahashi, Kazuya Ofuji,
Masahiro Ohtani, Hiroyuki Suto, Yasunari Nakamoto; University
of Fukui, Fukui, Japan
BACKGROUND: Hyperinsulinemia is well known to be associated
with type 2 diabetic patients. It remains unclear how
hyperinsulinemia contributes to progression of obesity, pathogenesis
of fatty liver and development of non-alcoholic steatohepatitis
(NASH). In the previous studies, inhibitor of DNA
binding 2 (Id2) gene, a dominant-negative transcriptional
repressor, has been shown to function as a promoting factor
for obesity. Here, we examined, in vitro and in vivo, whether
hyperinsulinemia causes promotion of obesity and pathogenesis
of fatty liver mediated by Id2 using type 2 diabetes
mellitus models. METHODS: Mouse fibroblast NIH-3T3 cells
and human hepatoma HepG2 cells were treated with various
concentrations of insulin, and Id2 mRNA and protein expression
were analyzed by Northern and Western blots. Mouse
preadipocyte 3T3-L1 cells were differentiated to adipocytes in
differentiation cocktail (insulin, 3-isobutyl-1-methylxanthine and
dexamethasone). KK-A y mice were used as a type 2 diabetes
mellitus model. Blood glucose was measured using a glucose
monitor, and serum insulin was measured by ELISA. Histological
examination was performed on liver specimens. KK-A y mice
were crossed with Id2 KO mice, and KK-A y -Id2 KO mice were
obtained. Mice had body weight recorded weekly. RESULTS:
Id2 expression at mRNA and protein levels in NIH-3T3 cells
and HepG2 cells was induced by insulin in a dose-dependent
manner. Id2 induction by insulin was partially inhibited by PI3
kinase inhibitor. 3T3-L1 cells expressed high amount of Id2
protein by addition of differentiation cocktail containing insulin
and differentiated to adipocytes. In contrast, the cells did
not differentiate by the cocktail lacking insulin. In KK-A y mice,
blood glucose and serum insulin (3.0 ng/ml) was significantly
higher compared to non-diabetic 129/Sv mice (0.58 ng/ml)
(P