Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice

Jan Freark de Boer, Marleen Schonewille, Marije Boesjes, Henk Wolters, Vincent W. Bloks, Trijnie Bos, Theo H. van Dijk, Angelika Jurdzinski, Renze Boverhof, Justina C. Wolters, Jan A. Kuivenhoven, Jan Van Deursen, Ronald P J Oude Elferink, Antonio Moschetta, Claus Kremoser, Henkjan J. Verkade, Folkert Kuipers, Albert K. Groen

Research output: Contribution to journalArticle

39 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1126-1138.e6
JournalGastroenterology
Volume152
Issue number5
DOIs
StatePublished - Apr 1 2017

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Cholesterol
Bile Acids and Salts
Bile
Intestines
Anticholesteremic Agents
Cholates
Diet
Fibroblast Growth Factors
Sterols
Bile Ducts
Transgenes
Hydrophobic and Hydrophilic Interactions
Knockout Mice
Intravenous Injections
Catheterization
Drinking Water
Wistar Rats
Acetates
Homeostasis
Cardiovascular Diseases

Keywords

  • ABCG5/G8
  • Bile Salts
  • Metabolism
  • RCT
  • TICE

ASJC Scopus subject areas

  • Gastroenterology

Cite this

de Boer, J. F., Schonewille, M., Boesjes, M., Wolters, H., Bloks, V. W., Bos, T., ... Groen, A. K. (2017). Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice. Gastroenterology, 152(5), 1126-1138.e6. https://doi.org/10.1053/j.gastro.2016.12.037

Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice. / de Boer, Jan Freark; Schonewille, Marleen; Boesjes, Marije; Wolters, Henk; Bloks, Vincent W.; Bos, Trijnie; van Dijk, Theo H.; Jurdzinski, Angelika; Boverhof, Renze; Wolters, Justina C.; Kuivenhoven, Jan A.; Van Deursen, Jan; Oude Elferink, Ronald P J; Moschetta, Antonio; Kremoser, Claus; Verkade, Henkjan J.; Kuipers, Folkert; Groen, Albert K.

In: Gastroenterology, Vol. 152, No. 5, 01.04.2017, p. 1126-1138.e6.

Research output: Contribution to journalArticle

de Boer, JF, Schonewille, M, Boesjes, M, Wolters, H, Bloks, VW, Bos, T, van Dijk, TH, Jurdzinski, A, Boverhof, R, Wolters, JC, Kuivenhoven, JA, Van Deursen, J, Oude Elferink, RPJ, Moschetta, A, Kremoser, C, Verkade, HJ, Kuipers, F & Groen, AK 2017, 'Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice', Gastroenterology, vol. 152, no. 5, pp. 1126-1138.e6. https://doi.org/10.1053/j.gastro.2016.12.037
de Boer JF, Schonewille M, Boesjes M, Wolters H, Bloks VW, Bos T et al. Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice. Gastroenterology. 2017 Apr 1;152(5):1126-1138.e6. https://doi.org/10.1053/j.gastro.2016.12.037
de Boer, Jan Freark ; Schonewille, Marleen ; Boesjes, Marije ; Wolters, Henk ; Bloks, Vincent W. ; Bos, Trijnie ; van Dijk, Theo H. ; Jurdzinski, Angelika ; Boverhof, Renze ; Wolters, Justina C. ; Kuivenhoven, Jan A. ; Van Deursen, Jan ; Oude Elferink, Ronald P J ; Moschetta, Antonio ; Kremoser, Claus ; Verkade, Henkjan J. ; Kuipers, Folkert ; Groen, Albert K. / Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice. In: Gastroenterology. 2017 ; Vol. 152, No. 5. pp. 1126-1138.e6.
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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.",
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AU - de Boer, Jan Freark

AU - Schonewille, Marleen

AU - Boesjes, Marije

AU - Wolters, Henk

AU - Bloks, Vincent W.

AU - Bos, Trijnie

AU - van Dijk, Theo H.

AU - Jurdzinski, Angelika

AU - Boverhof, Renze

AU - Wolters, Justina C.

AU - Kuivenhoven, Jan A.

AU - Van Deursen, Jan

AU - Oude Elferink, Ronald P J

AU - Moschetta, Antonio

AU - Kremoser, Claus

AU - Verkade, Henkjan J.

AU - Kuipers, Folkert

AU - Groen, Albert K.

PY - 2017/4/1

Y1 - 2017/4/1

N2 - 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.

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