Jan Freark de Boer1, Marleen Schonewille2, Marije Boesjes2, Henk Wolters2, Vincent W Bloks2, Trijnie Bos3, Theo H van Dijk3, Angelika Jurdzinski2, Renze Boverhof3, Justina C Wolters2, Jan A Kuivenhoven2, Jan M van Deursen4, Ronald P J Oude Elferink5, Antonio Moschetta6, Claus Kremoser7, Henkjan J Verkade2, Folkert Kuipers8, Albert K Groen8. 1. Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address: j.f.de.boer@umcg.nl. 2. Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 3. Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 4. Department of Pediatric and Adolescent Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota. 5. Tytgat Institute for Liver and Intestinal Research, Department of Hepatology and Gastroenterology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. 6. Department of Interdisciplinary Medicine, University of Bari, IRCCS Istituto Tumori "Giovanni Paolo II," Bari, Italy. 7. Phenex Pharmaceuticals AG, Heidelberg, Germany. 8. Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Abstract
BACKGROUND & AIMS: The role of the intestine in the maintenance of cholesterol homeostasis increasingly is recognized. Fecal excretion of cholesterol is the last step in the atheroprotective reverse cholesterol transport pathway, to which biliary and transintestinal cholesterol excretion (TICE) contribute. The mechanisms controlling the flux of cholesterol through the TICE pathway, however, are poorly understood. We aimed to identify mechanisms that regulate and stimulate TICE. METHODS: We performed studies with C57Bl/6J mice, as well as with mice with intestine-specific knockout of the farnesoid X receptor (FXR), mice that express an FXR transgene specifically in the intestine, and ABCG8-knockout mice. Mice were fed a control diet or a diet supplemented with the FXR agonist PX20606, with or without the cholesterol absorption inhibitor ezetimibe. Some mice with intestine-specific knockout of FXR were given daily injections of fibroblast growth factor (FGF)19. To determine fractional cholesterol absorption, mice were given intravenous injections of cholesterol D5 and oral cholesterol D7. Mice were given 13C-acetate in drinking water for measurement of cholesterol synthesis. Bile cannulations were performed and biliary cholesterol secretion rates were assessed. In a separate set of experiments, bile ducts of male Wistar rats were exteriorized, allowing replacement of endogenous bile by a model bile. RESULTS: In mice, we found TICE to be regulated by intestinal FXR via induction of its target gene Fgf15 (FGF19 in rats and human beings). Stimulation of this pathway caused mice to excrete up to 60% of their total cholesterol content each day. PX20606 and FGF19 each increased the ratio of muricholate:cholate in bile, inducing a more hydrophilic bile salt pool. The altered bile salt pool stimulated robust secretion of cholesterol into the intestinal lumen via the sterol-exporting heterodimer adenosine triphosphate binding cassette subfamily G member 5/8 (ABCG5/G8). Of note, the increase in TICE induced by PX20606 was independent of changes in cholesterol absorption. CONCLUSIONS: Hydrophilicity of the bile salt pool, controlled by FXR and FGF15/19, is an important determinant of cholesterol removal via TICE. Strategies that alter bile salt pool composition might be developed for the prevention of cardiovascular disease. Transcript profiling: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=irsrayeohfcntqx&acc=GSE74101.
BACKGROUND & AIMS: The role of the intestine in the maintenance of cholesterol homeostasis increasingly is recognized. Fecal excretion of cholesterol is the last step in the atheroprotective reverse cholesterol transport pathway, to which biliary and transintestinal cholesterol excretion (TICE) contribute. The mechanisms controlling the flux of cholesterol through the TICE pathway, however, are poorly understood. We aimed to identify mechanisms that regulate and stimulate TICE. METHODS: We performed studies with C57Bl/6J mice, as well as with mice with intestine-specific knockout of the farnesoid X receptor (FXR), mice that express an FXR transgene specifically in the intestine, and ABCG8-knockout mice. Mice were fed a control diet or a diet supplemented with the FXR agonist PX20606, with or without the cholesterol absorption inhibitor ezetimibe. Some mice with intestine-specific knockout of FXR were given daily injections of fibroblast growth factor (FGF)19. To determine fractional cholesterol absorption, mice were given intravenous injections of cholesterol D5 and oral cholesterol D7. Mice were given 13C-acetate in drinking water for measurement of cholesterol synthesis. Bile cannulations were performed and biliary cholesterol secretion rates were assessed. In a separate set of experiments, bile ducts of male Wistar rats were exteriorized, allowing replacement of endogenous bile by a model bile. RESULTS: In mice, we found TICE to be regulated by intestinal FXR via induction of its target gene Fgf15 (FGF19 in rats and human beings). Stimulation of this pathway caused mice to excrete up to 60% of their total cholesterol content each day. PX20606 and FGF19 each increased the ratio of muricholate:cholate in bile, inducing a more hydrophilic bile salt pool. The altered bile salt pool stimulated robust secretion of cholesterol into the intestinal lumen via the sterol-exporting heterodimer adenosine triphosphate binding cassette subfamily G member 5/8 (ABCG5/G8). Of note, the increase in TICE induced by PX20606 was independent of changes in cholesterol absorption. CONCLUSIONS: Hydrophilicity of the bile salt pool, controlled by FXR and FGF15/19, is an important determinant of cholesterol removal via TICE. Strategies that alter bile salt pool composition might be developed for the prevention of cardiovascular disease. Transcript profiling: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=irsrayeohfcntqx&acc=GSE74101.
Authors: Jianing Li; Sonja S Pijut; Yuhuan Wang; Ailing Ji; Rupinder Kaur; Ryan E Temel; Deneys R van der Westhuyzen; Gregory A Graf Journal: Arterioscler Thromb Vasc Biol Date: 2019-08-29 Impact factor: 8.311
Authors: C Blanchard; F Moreau; A Ayer; L Toque; D Garçon; L Arnaud; F Borel; A Aguesse; M Croyal; M Krempf; X Prieur; M Neunlist; B Cariou; C Le May Journal: Int J Obes (Lond) Date: 2017-09-28 Impact factor: 5.095
Authors: Christina Gallo-Ebert; Jamie Francisco; Hsing-Yin Liu; Riley Draper; Kinnari Modi; Michael D Hayward; Beverly K Jones; Olesia Buiakova; Virginia McDonough; Joseph T Nickels Journal: J Biol Chem Date: 2018-02-28 Impact factor: 5.157
Authors: Ivo P van de Peppel; Anna Bertolini; Theo H van Dijk; Albert K Groen; Johan W Jonker; Henkjan J Verkade Journal: J Lipid Res Date: 2019-07-19 Impact factor: 5.922
Authors: Romeo Papazyan; Xueqing Liu; Jingwen Liu; Bin Dong; Emily M Plummer; Ronald D Lewis; Jonathan D Roth; Mark A Young Journal: J Lipid Res Date: 2018-03-20 Impact factor: 5.922