Non-alcoholic fatty liver disease (
NAFLD) is a major growing worldwide health problem. We previously reported that interruption of the enterohepatic circulation of
bile acids using a non-absorbable
apical sodium-dependent bile acid transporter inhibitor (ASBTi;
SC-435) reduced the development of
NAFLD in high fat diet fed mice. However, the ability of ASBTi treatment to impact the progression of
NAFLD to non-
alcoholic steatohepatitis (NASH) and
fibrosis in a diet-induced mouse model remains untested. In the current study, we assessed whether ASBTi treatment is hepatoprotective in the
choline-deficient, L-
amino acid-defined (
CDAA) diet model of NASH-induced
fibrosis. Methods: Male C57Bl/6 mice were fed with: (A)
choline-sufficient L-
amino acid-defined diet (CSAA) (31 kcal% fat), (B) CSAA diet plus ASBTi (
SC-435; 60 ppm), (C)
CDAA diet, or (D)
CDAA diet plus ASBTi.
Body weight and food intake were monitored. After 22 weeks on diet, liver histology,
cholesterol and
triglyceride levels, and gene expression were measured. Fecal
bile acid and fat excretion were measured, and intestinal fat absorption was determined using the
sucrose polybehenate method. Results: ASBTi treatment reduced bodyweight gain in mice fed either the CSAA or
CDAA diet, and prevented the increase in liver to
body weight ratio observed in
CDAA-fed mice. ASBTi significantly reduced hepatic total
cholesterol levels in both CSAA and
CDAA-fed mice. ASBTi-associated significant reductions in hepatic
triglyceride levels and histological scoring for
NAFLD activity were observed in CSAA but not
CDAA-fed mice. These changes correlated with measurements of intestinal fat absorption, which was significantly reduced in ASBTi-treated mice fed the CSAA (85 vs. 94%, P < 0.001) but not
CDAA diet (93 vs. 93%). As scored by Ishak staging of Sirius red stained liver sections, no hepatic
fibrosis was evident in the CSAA diet mice. The
CDAA diet-fed mice developed hepatic
fibrosis, which was increased by the ASBTi. Conclusions: ASBT inhibition reduced intestinal fat absorption, bodyweight gain and hepatic steatosis in CSAA diet-fed mice. The effects of the ASBTi on steatosis and fat absorption were attenuated in the context of dietary
choline-deficiency. Inhibition of intestinal absorption of
fatty acids may be involved in the
therapeutic effects of ASBTi treatment.