Inhibition of ileal bile acid uptake protects against nonalcoholic fatty liver disease in high-fat diet-fed mice

• Type of Material: Article
• Authors: Anuradha Rao, Emory University; Astrid Kosters, Emory University; Jamie E. Mells, Emory University; Wujuan Zhang, Cincinnati Childrens Hosp Med Ctr; Kenneth D. R. Setchell, Cincinnati Childrens Hosp Med Ctr; Angelica Amanso, Emory University; Grace M. Wynn, Emory University; Tianlei Xu, Emory University; Brad T. Keller, Vasculox Inc; Hong Yin, Childrens Healthcare Atlanta; Sophia Banton, Emory University; Dean Jones, Emory University; Hao Wu, Emory University; Paul Dawson, Emory University; Saul Karpen, Emory University
• Language: English
• Date: 2016-09-21
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2016, American Association for the Advancement of Science
• Final Published Version (URL): http://dx.doi.org/10.1126/scitranslmed.aaf4823
• Title of Journal or Parent Work: Science Translational Medicine
• ISSN: 1946-6234
• Volume: 8
• Issue: 357
• Start Page: 357ra122
• End Page: 357ra122
• Grant/Funding Information: The studies were supported by NIH (DK56239 SJK; DK047987 PAD; ES023485, AG038746, HL113451, ES019776, ES025632, EY022618, HD075784, HL095479, HL086773, HL125042 DPJ).; JEM was supported by an NIH Fellowship in Research and Science Teaching (FIRST) Institutional Research and Academic Career Development Award (K12 GM000680).; SJK and PAD were also supported by the Center for Transplantation and Immune-Mediated Disorders and Children’s Healthcare of Atlanta.
• Keywords: Cell Biology; Medicine, Research & Experimental; OBESITY; MICROBIOTA; Research & Experimental Medicine; STEATOHEPATITIS; NASH; LIPID-METABOLISM; CHOLESTEROL; METABOLIC SYNDROME; Science & Technology; NUCLEAR RECEPTOR; Life Sciences & Biomedicine; DIABETIC MICE; FXR
• Research Categories: Health Sciences, Nutrition; Health Sciences, Pathology; Chemistry, Biochemistry

Abstract

Nonalcoholic fatty liver disease (NAFLD) is themost 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) wouldmodify 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 amarked 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 HFDfed 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.