Inhibition of ileal bile acid uptake protects against nonalcoholic fatty liver disease in high-fat diet-fed mice
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...
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Published in | Science translational medicine Vol. 8; no. 357; p. 357ra122 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
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21.09.2016
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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. |
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AbstractList | 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. |
Author | Amanso, Angelica M Xu, Tianlei Wu, Hao Rao, Anuradha Kosters, Astrid Wynn, Grace M Jones, Dean P Setchell, Kenneth D R Banton, Sophia Karpen, Saul J Mells, Jamie E Keller, Brad T Zhang, Wujuan Yin, Hong Dawson, Paul A |
Author_xml | – sequence: 1 givenname: Anuradha surname: Rao fullname: Rao, Anuradha organization: Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA – sequence: 2 givenname: Astrid surname: Kosters fullname: Kosters, Astrid organization: Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA – sequence: 3 givenname: Jamie E surname: Mells fullname: Mells, Jamie E organization: Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA – sequence: 4 givenname: Wujuan surname: Zhang fullname: Zhang, Wujuan organization: Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA – sequence: 5 givenname: Kenneth D R surname: Setchell fullname: Setchell, Kenneth D R organization: Department of Pathology and Laboratory Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229, USA – sequence: 6 givenname: Angelica M surname: Amanso fullname: Amanso, Angelica M organization: Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA – sequence: 7 givenname: Grace M surname: Wynn fullname: Wynn, Grace M organization: Department of Pediatrics, Emory University School of Medicine, 1760 Haygood Drive Northeast, Atlanta, GA 30322, USA – sequence: 8 givenname: Tianlei surname: Xu fullname: Xu, Tianlei organization: Department of Mathematics and Computer Science, Emory University, Atlanta, GA 30322, USA – sequence: 9 givenname: Brad T surname: Keller fullname: Keller, Brad T organization: Vasculox Inc., St. Louis, MO 63108, USA – sequence: 10 givenname: Hong surname: Yin fullname: Yin, Hong organization: Children's Healthcare of Atlanta, 2015 Uppergate Drive Northeast, Atlanta, GA 30322, USA – sequence: 11 givenname: Sophia surname: Banton fullname: Banton, Sophia organization: Department of Biochemistry, Emory University, 1510 Clifton Road Northeast, Atlanta, GA 30322, USA – sequence: 12 givenname: Dean P surname: Jones fullname: Jones, Dean P organization: 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 – sequence: 13 givenname: Hao surname: Wu fullname: Wu, Hao organization: Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA – sequence: 14 givenname: Paul A surname: Dawson fullname: Dawson, Paul A organization: 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 – sequence: 15 givenname: Saul J surname: Karpen fullname: Karpen, Saul J email: skarpen@emory.edu organization: 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 |
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Snippet | 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... |
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SubjectTerms | Animals Bile Acids and Salts - metabolism Ceramides - metabolism Cholesterol - metabolism Cyclic N-Oxides - administration & dosage Cyclic N-Oxides - pharmacology Diet, High-Fat - adverse effects Feces Gene Expression Regulation - drug effects Glucose Tolerance Test Ileum - drug effects Ileum - metabolism Liver - drug effects Liver - metabolism Mice, Inbred C57BL Non-alcoholic Fatty Liver Disease - pathology Non-alcoholic Fatty Liver Disease - prevention & control Organic Anion Transporters, Sodium-Dependent - deficiency Organic Anion Transporters, Sodium-Dependent - metabolism Receptors, Cytoplasmic and Nuclear - agonists Receptors, Cytoplasmic and Nuclear - metabolism Symporters - deficiency Symporters - metabolism Triglycerides - metabolism Tropanes - administration & dosage Tropanes - pharmacology |
Title | Inhibition of ileal bile acid uptake protects against nonalcoholic fatty liver disease in high-fat diet-fed mice |
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