title: Inhibition of ileal bile acid uptake protects against nonalcoholic fatty liver disease in high-fat diet-fed mice.
abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and safe and effective therapies are needed. Bile acids (BAs) and their receptors [including the nuclear receptor for BAs, farnesoid X receptor (FXR)] play integral roles in regulating whole-body metabolism and hepatic lipid homeostasis. We hypothesized that interruption of the enterohepatic BA circulation using a luminally restricted apical sodium-dependent BA transporter (ASBT) inhibitor (ASBTi; SC-435) would modify signaling in the gut-liver axis and reduce steatohepatitis in high-fat diet (HFD)-fed mice. Administration of this ASBTi increased fecal BA excretion and messenger RNA (mRNA) expression of BA synthesis genes in liver and reduced mRNA expression of ileal BA-responsive genes, including the negative feedback regulator of BA synthesis, fibroblast growth factor 15. ASBT inhibition resulted in a marked shift in hepatic BA composition, with a reduction in hydrophilic, FXR antagonistic species and an increase in FXR agonistic BAs. ASBT inhibition restored glucose tolerance, reduced hepatic triglyceride and total cholesterol concentrations, and improved NAFLD activity score in HFD-fed mice. These changes were associated with reduced hepatic expression of lipid synthesis genes (including liver X receptor target genes) and normalized expression of the central lipogenic transcription factor, Srebp1c Accumulation of hepatic lipids and SREBP1 protein were markedly reduced in HFD-fed Asbt(-/-) mice, providing genetic evidence for a protective role mediated by interruption of the enterohepatic BA circulation. Together, these studies suggest that blocking ASBT function with a luminally restricted inhibitor can improve both hepatic and whole body aspects of NAFLD.
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Rao
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA.
authors.forename: Astrid
authors.initials: A
authors.lastname: Kosters
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Mells
authors.affiliation: Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Wujuan
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA.
authors.forename: Kenneth D R
authors.initials: KD
authors.lastname: Setchell
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA.
authors.forename: Angelica M
authors.initials: AM
authors.lastname: Amanso
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA.
authors.forename: Grace M
authors.initials: GM
authors.lastname: Wynn
authors.affiliation: Department of Mathematics and Computer Science, Emory University, Atlanta, GA 30322, USA.
authors.forename: Tianlei
authors.initials: T
authors.lastname: Xu
authors.affiliation: Vasculox Inc., St. Louis, MO 63108, USA.
authors.forename: Brad T
authors.initials: BT
authors.lastname: Keller
authors.affiliation: Children's Healthcare of Atlanta, 2015 Uppergate Drive Northeast, Atlanta, GA 30322, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Yin
authors.affiliation: Department of Biochemistry, Emory University, 1510 Clifton Road Northeast, Atlanta, GA 30322, USA.
authors.forename: Sophia
authors.initials: S
authors.lastname: Banton
authors.affiliation: Department of Biochemistry, Emory University, 1510 Clifton Road Northeast, Atlanta, GA 30322, USA. Department of Medicine, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322, USA.
authors.forename: Dean P
authors.initials: DP
authors.lastname: Jones
authors.affiliation: Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA. Children's Healthcare of Atlanta, 2015 Uppergate Drive Northeast, Atlanta, GA 30322, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dawson
authors.affiliation: Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA. Children's Healthcare of Atlanta, 2015 Uppergate Drive Northeast, Atlanta, GA 30322, USA. skarpen@emory.edu.
authors.forename: Saul J
authors.initials: SJ
authors.lastname: Karpen
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002518:Ceramides / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000008:administration & dosage / Q000494:pharmacology; D059305:Diet, High-Fat / Q000009:adverse effects*; D005243:Feces; D005786:Gene Expression Regulation / Q000187:drug effects; D005951:Glucose Tolerance Test; D007082:Ileum / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000473:pathology* / Q000517:prevention & control*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000172:deficiency / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism; D027981:Symporters / Q000172:deficiency / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D014326:Tropanes / Q000008:administration & dosage / Q000494:pharmacology; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002518:Ceramides; D002784:Cholesterol; D003497:Cyclic N-Oxides; D029363:Organic Anion Transporters, Sodium-Dependent; D018160:Receptors, Cytoplasmic and Nuclear; D027981:Symporters; D014280:Triglycerides; D014326:Tropanes; D000099150:Receptor, Farnesoid X-Activated; C466800:1-(4-(4-(3,3-dibutyl-7-(dimethylamino)-2,3,4,5-tetrahydro-4-hydroxy-1,1-dioxido-1-benzothiepin-5-yl)phenoxy)butyl)-4-aza-1-azoniabicyclo(2.2.2)octane; C071908:sodium-bile acid cotransporter