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• W3154524653 abstract "Abstract 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 disease severity. Pharmacological agents targeting bile acid metabolism and signaling may be potential therapeutics for ALD. Methods The potential beneficial effects of a gut‐restricted apical sodium‐dependent bile acid transporter (ASBT) inhibitor were studied in a chronic‐plus‐binge ALD mouse model. Results Blocking intestinal bile acid reabsorption by the gut‐restricted ASBT inhibitor GSK2330672 attenuated hepatic steatosis and liver injury in a chronic‐plus‐binge ALD mouse model. Alcohol feeding is associated with intestinal bile acid accumulation but paradoxically impaired ileal farnesoid × receptor (FXR) function, and repressed hepatic cholesterol 7α‐hydrolase (CYP7A1) expression despite decreased hepatic small heterodimer partner (SHP) and ileal fibroblast growth factor 15 (FGF15) expression. ASBT inhibitor treatment decreased intestinal bile acid accumulation and increased hepatic CYP7A1 expression, but further decreased ileal FXR activity. Alcohol feeding induces serum bile acid concentration that strongly correlates with a liver injury marker. However, alcohol‐induced serum bile acid elevation is not due to intrahepatic bile acid accumulation but is strongly and positively associated with hepatic multidrug resistance‐associated protein 3 (MRP4) and MRP4 induction but poorly associated with sodium‐taurocholate cotransporting peptide (NTCP) expression. ASBT inhibitor treatment decreases serum bile acid concentration without affecting hepatocyte basolateral bile acid uptake and efflux transporters. Conclusion ASBT inhibitor treatment corrects alcohol‐induced bile acid dysregulation and attenuates liver injury in experimental ALD." @default.
• W3154524653 created "2021-04-26" @default.
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• W3154524653 date "2021-05-11" @default.
• W3154524653 modified "2023-10-17" @default.
• W3154524653 title "Gut‐restricted apical sodium‐dependent bile acid transporter inhibitor attenuates alcohol‐induced liver steatosis and injury in mice" @default.
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• W3154524653 doi "https://doi.org/10.1111/acer.14619" @default.
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