Gut-restricted apical sodium-dependent bile acid transporter inhibitor attenuates alcohol-induced liver steatosis and injury in mice.
作者： Yuan Li , Cheng Chen , Huaiwen Wang , Tiangang Li , Wen-Xing Ding
DOI: 10.1111/ACER.14619
关键词: FGF15 、 Endocrinology 、 Chemistry 、 Liver injury 、 Internal medicine 、 Small heterodimer partner 、 Liver disease 、 Cholesterol 7 alpha-hydroxylase 、 Bile acid 、 Steatosis 、 Hepatocyte
摘要: BACKGROUND Recent studies have shown that human and experimental alcohol-related liver disease (ALD) is robustly associated with dysregulation of bile acid homeostasis, which may in turn modulate severity. Pharmacological agents targeting metabolism signaling be potential therapeutics for ALD. METHODS The beneficial effects a gut-restricted apical sodium-dependent transporter (ASBT) inhibitor were studied chronic-plus-binge ALD mouse model. RESULTS Blocking intestinal reabsorption by the ASBT GSK2330672 attenuated hepatic steatosis injury Alcohol feeding accumulation but paradoxically impaired ileal farnesoid × receptor (FXR) function, repressed cholesterol 7α-hydrolase (CYP7A1) expression despite decreased small heterodimer partner (SHP) fibroblast growth factor 15 (FGF15) expression. treatment increased CYP7A1 expression, further FXR activity. induces serum concentration strongly correlates marker. However, alcohol-induced elevation not due to intrahepatic positively multidrug resistance-associated protein 3 (MRP4) MRP4 induction poorly sodium-taurocholate cotransporting peptide (NTCP) decreases without affecting hepatocyte basolateral uptake efflux transporters. CONCLUSION corrects attenuates
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