Gut-restricted apical sodium-dependent bile acid transporter inhibitor attenuates alcohol-induced liver steatosis and injury in mice.

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.

• Authors: David J Matye, Yuan Li, Cheng Chen, Xiaojuan Chao, Huaiwen Wang, Hongmin Ni, Wen-Xing Ding, Tiangang Li
• Journal: Alcoholism, clinical and experimental research (Alcohol Clin Exp Res) Vol. 45 Issue 6 Pg. 1188-1199 (06 2021) ISSN: 1530-0277 [Electronic] England
• PMID: 33885179 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2021 by the Research Society on Alcoholism.

Chemical References

• 3-((((3R,5R)-3-butyl-3-ethyl-7-(methyloxy)-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydro-1,4-benzothiazepin-8-yl)methyl)amino)pentanedioic acid
• Abcc4 protein, mouse
• Angiogenic Proteins
• Bile Acids and Salts
• Methylamines
• Multidrug Resistance-Associated Proteins
• Organic Anion Transporters, Sodium-Dependent
• Symporters
• Thiazepines
• mitogen-regulated protein 3, mouse
• sodium-bile acid cotransporter
• Transaminases

Topics

• Angiogenic Proteins (metabolism)
• Animals
• Bile Acids and Salts (blood)
• Drug Evaluation, Preclinical
• Lipid Metabolism (drug effects)
• Liver (drug effects, metabolism)
• Liver Diseases, Alcoholic (drug therapy)
• Male
• Methylamines (pharmacology, therapeutic use)
• Mice, Inbred C57BL
• Multidrug Resistance-Associated Proteins (metabolism)
• Organic Anion Transporters, Sodium-Dependent (antagonists & inhibitors)
• Symporters (antagonists & inhibitors)
• Thiazepines (pharmacology, therapeutic use)
• Transaminases (blood)