studies

280A AASLD ABSTRACTS HEPATOLOGY, October, 2015
and risk for liver disease in AATD is needed to direct screening
and novel therapies toward patients who could benefit most.
In this cross section of older AATD subjects, over one-third had
clinically significant liver fibrosis confirmed by biopsy. This is
much higher than our previously reported prevalence of 7.9%
using patient self-reported data. We also confirmed our previous
finding that ALT and GGT for affected subjects fall within
normal range, which limits clinical utility. The histologic spectrum
was varied both in fibrosis and qualitative presence of
AATD globules. Future studies will evaluate clinical risk factors
and predictors for advanced liver disease.
Disclosures:
The following authors have nothing to disclose: Virginia C. Clark, George W.
Marek, Tracie L. Kurtz, Chen Liu, Farshid Rouhani, Mark Brantly
139
Bile Acid Sequestrant Prevents NAFLD and NASH in
Western Diet Fed Mice Independent of FXR
Yuhuan Luo 1 , Xiaoxin Wang 1 , David J. Orlicky 2 , Moshe Levi 1 ;
1 Medicine, Univ Colorado, Aurora, CO; 2 Pathology, University of
Colorado, Aurora, CO
Bile acid sequestrants (BAS) are orally administered nonabsorbable
polymers that decrease serum cholesterol and serum glucose
in patients and animal models of type 2 diabetes mellitus.
We evaluated the effect of the BAS sevelamer in mice with diet
induced obesity and insulin resistance that develop NAFLD and
NASH. C57BL/6J male mice were fed with 1) control low fat
(LF) diet or 2) western (WD) diet (high fat, high sucrose, cholesterol)
for 5 months. The diets contained a) no addition or b) 2%
sevelamer. Treatment with sevelamer prevented the increases
in body weight, liver weight, serum triglycerides and serum
cholesterol. Histopathological analysis revealed diet induced
NAFLD and NASH mouse model resulted in panlobular macrosteatosis
with some microvesicular steatosis, and increases in
peri-portal inflammation and peri-portal and zone 1 sinusoidal
fibrosis extending into zones 2 & 3 in places. Sevelamer treatment
significantly decreased steatosis, inflammation and fibrosis
scores. There was decreased FXR signaling in the intestine
and the liver (FGF15 and SHP in the intestine as well as SHP
in the liver). There was also increased liver bile acid synthesis
(Cyp7a1) and expression of bile acid transporters. In addition,
there were significant decreases in SREBP-1c, ACC and FAS,
resulting in decreased neutral lipid accumulation. Sevelamer
also prevented or reversed WD-induced upregulation of profibrotic
(COL1A1, α-SMA, TGF-β) and proinflammatory (CCL2,
IL-1β, and TNF-α) genes in the liver. These effects of sevelamer
were independent of FXR as in FXR KO mice fed a western diet
sevelamer had similar beneficial effects in improving NAFLD/
NASH as in wild type mice. BAS treatment therefore prevents
diet induced NAFLD and NASH. This beneficial effect is largely
independent of FXR but may be mediated through activation of
the TGR5 signaling pathway.
Disclosures:
Moshe Levi - Grant/Research Support: Intercept, Genzyme-Sanofi, Daiichi Sankyo,
Merck, Novartis
The following authors have nothing to disclose: Yuhuan Luo, Xiaoxin Wang,
David J. Orlicky
140
Targeting enterohepatic bile acid signaling as a novel
approach to modulate hepatic autophagic activity in
maintaining cholesterol homeostasis
Yifeng Wang, Yifeng Ding, Hong-Min Ni, Wen-Xing Ding, Tiangang
Li; Pharmacolgy, KUMC, Kansas City, KS
Liver plays a key role in whole body cholesterol homeostasis.
In addition, hepatic free cholesterol accumulation results in
hepatocyte injury in non-alcoholic steatohepatitis (NASH). Lysosomes
play an important role in maintaining cellular cholesterol
homeostasis by regulating cholesterol ester hydrolysis that
affects pathways such as cholesterol uptake, secretion and bile
acid synthesis. New studies revealed that autophagy mediates
the cellular transport of cholesterol ester from lipid droplets to
lysosomes. Goal: this study investigated the role and regulation
of hepatic autophagy in cholesterol metabolism. Methods: the
effect of cholesterol accumulation on autophagy flux and lysosome
function was investigated in hepatocytes and in mice.
The impact of autophagy impairment on hepatic and plasma
cholesterol metabolism was studied in liver-specific ATG5
knockout mice. The effect of cholestyramine on hepatic autophagy
was studied in mice. Results: Feeding mice a cholesterol-containing
diet or an atherogenic diet for 6 days increased
liver LC3-II and p62 levels in response to hepatic cholesterol
accumulation. Both free cholesterol loading and treatment with
low density lipoprotein (LDL) increased LC3B-II and p62 levels
in human hepatocytes and HepG2 cells, however, only free
cholesterol loading, but not LDL treatment, increased lysosome
size and decreased cathepsin B activities in HepG2 cells, suggesting
free cholesterol accumulation can also impair lysosome
function. Consistently, inhibition of cholesterol esterification
with an ACAT inhibitor to increase cellular free cholesterol
levels blocked autophagosome/lysosome fusion and caused
CASPASE-3 activation in HepG2 cells. In autophagy-defective
liver-specific ATG5 knockout mice, hepatic cholesterol was
unchanged, but FPLC analysis showed that plasma LDL-cholesterol
was significantly elevated. As previous studies suggested
that autophagy was impaired in NASH, we found that cholestyramine
feeding increased hepatic autophagy in both lean
and ob/ob mice, which was possibly due to the removal of
bile acid-mediated inhibition of autophagosome/lysosome
fusion. Conclusion: this study suggests that hepatic autophagy
is required for maintaining whole body cholesterol homeostasis.
Hepatic free cholesterol accumulation impairs hepatic
autophagy, which exacerbates hypercholesterolemia and
hepatocyte-injury in NASH. As we recently showed that bile
acids inhibit hepatic autophagy, targeting enterohepatic bile
acid signaling by bile acid binding resin may be an effective
approach to induce hepatic autophagy and attenuate cholesterol-induced
liver injury.
Disclosures:
The following authors have nothing to disclose: Yifeng Wang, Yifeng Ding, Hong-
Min Ni, Wen-Xing Ding, Tiangang Li
141
Anti-Fibrotic Effect of Autotaxin and LPA1R Antagonists
in a Rodent Model of NASH.
Malavi Madireddi 1 , Gretchen Bain 3 , James Swaney 2 , Brian J.
Murphy 1 , Simeon Taylor 1 ; 1 Metabolic and Fibrotic Diseases, Bristol
Myers Squibb, West Windsor, NJ; 2 Inception Sciences, San
Diego, CA; 3 PharmAkea, Inc., San Diego, CA
Nonalcoholic steatohepatitis (NASH) is a condition where
increased fat accumulation concomitant with inflammation
results in liver cell damage. Patients with NASH have elevated