studies

HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 217A
19
Administration of an Ileal Apical Sodium-dependent Bile
Acid Transporter Inhibitor Protects Against Non-alcoholic
Fatty Liver Disease in High Fat Diet-fed Mice
Anuradha Rao 1 , Astrid Kosters 1 , Jamie Mells 1 , Bradley T. Keller 4 ,
Hong Yin 2 , Sophia Banton 2 , Shuzhao Li 2 , Dean P. Jones 2 , Hao
Wu 3 , Paul Dawson 1 , Saul J. Karpen 1 ; 1 Pediatrics, Emory University,
Atlanta, GA; 2 Medicine, Emory University, Atlanta, GA; 3 Public
Health, Emory University, Atlanta, GA; 4 Vasculox, Inc, St. Louis,
MO
Non-alcoholic fatty liver disease (NAFLD) is the most common
chronic liver disease in the Western world. The mechanisms
underlying NAFLD development and progression are not
fully elucidated, and safe and effective NAFLD therapies are
needed. Bile acids (BA) and their receptors have important
roles in regulating whole body metabolism, including multiple
hepatic targets coordinating lipid handling. We hypothesized
that interruption of the enterohepatic BA circulation via
a non-absorbable Apical Sodium-dependent BA Transporter
(ASBT) inhibitor (ASBTi; SC435) would modify signaling in
the gut-liver axis and diminish the development of NAFLD in
High Fat Diet (HFD) fed mice. Methods: Male C57Bl/6 mice
(n=12-16/group) were fed for 16 weeks with A) chow, B) HFD
composed of 45% fat and 0.2% cholesterol, with 4% sucrose
water (HFD), and C) HFD plus ASBTi (SC435; 60 ppm; HFD/
ASBTi). Body weight, food intake, glucose and insulin tolerance,
liver histology, and liver lipids were measured. Molecular
mechanisms were examined using RNASeq, metabolomics,
and real-time PCR analyses. Results: In HFD versus HFD/ASBTi
mice, administration of the ASBTi increased fecal BA excretion,
and mRNA expression for colonic Ibabp (7.0±2.0 fold;
p