Liver X Receptor Regulates Triglyceride Absorption Through Intestinal Down-regulation of Scavenger Receptor Class B, Type 1

Olivier Briand; Véronique Touche; Sophie Colin; Gemma Brufau; Alberto Davalos; Marleen Schonewille; Fabiola Bovenga; Véronique Carrière; Jan Freark De Boer; Camille Dugardin; Béatrice Riveau; Véronique Clavey; Anne Tailleux; Antonio Moschetta; Miguel A. Lasunción; Albert K. Groen; Bart Staels; Sophie Lestavel

doi:10.1053/j.gastro.2015.11.015

Liver X Receptor Regulates Triglyceride Absorption Through Intestinal Down-regulation of Scavenger Receptor Class B, Type 1

Olivier Briand, Véronique Touche, Sophie Colin, Gemma Brufau, Alberto Davalos, Marleen Schonewille, Fabiola Bovenga, Véronique Carrière, Jan Freark De Boer, Camille Dugardin, Béatrice Riveau, Véronique Clavey, Anne Tailleux, Antonio Moschetta, Miguel A. Lasunción, Albert K. Groen, Bart Staels, Sophie Lestavel

Pharmacology

Research output: Contribution to journal › Article › peer-review

39 Scopus citations

Abstract

Background & Aims Reducing postprandial triglyceridemia may be a promising strategy to lower the risk of cardiovascular disorders associated with obesity and type 2 diabetes. In enterocytes, scavenger receptor class B, type 1 (SR-B1, encoded by SCARB1) mediates lipid-micelle sensing to promote assembly and secretion of chylomicrons. The nuclear receptor subfamily 1, group H, members 2 and 3 (also known as liver X receptors [LXRs]) regulate genes involved in cholesterol and fatty acid metabolism. We aimed to determine whether intestinal LXRs regulate triglyceride absorption. Methods C57BL/6J mice were either fed a cholesterol-enriched diet or given synthetic LXR agonists (GW3965 or T0901317). We measured the production of chylomicrons and localized SR-B1 by immunohistochemistry. Mechanisms of postprandial triglyceridemia and SR-B1 regulation were studied in Caco-2/TC7 cells incubated with LXR agonists. Results In mice and in the Caco-2/TC7 cell line, LXR agonists caused localization of intestinal SR-B1 from apical membranes to intracellular organelles and reduced chylomicron secretion. In Caco-2/TC7 cells, LXR agonists reduced SR-B1-dependent lipidic-micelle-induced Erk phosphorylation. LXR agonists also reduced intracellular trafficking of the apical apolipoprotein B pool toward secretory compartments. LXR reduced levels of SR-B1 in Caco-2/TC7 cells via a post-transcriptional mechanism that involves microRNAs. Conclusion In Caco-2/TC7 cells and mice, intestinal activation of LXR reduces the production of chylomicrons by a mechanism dependent on the apical localization of SR-B1.

Original language	English (US)
Pages (from-to)	650-658
Number of pages	9
Journal	Gastroenterology
Volume	150
Issue number	3
DOIs	https://doi.org/10.1053/j.gastro.2015.11.015
State	Published - Mar 1 2016

Keywords

Fat Absorption
Hypertriglyceridemia
Lipid-Sensing
Triglyceride-Rich Lipoproteins

ASJC Scopus subject areas

Hepatology
Gastroenterology

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10.1053/j.gastro.2015.11.015

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Briand, O., Touche, V., Colin, S., Brufau, G., Davalos, A., Schonewille, M., Bovenga, F., Carrière, V., De Boer, J. F., Dugardin, C., Riveau, B., Clavey, V., Tailleux, A., Moschetta, A., Lasunción, M. A., Groen, A. K., Staels, B., & Lestavel, S. (2016). Liver X Receptor Regulates Triglyceride Absorption Through Intestinal Down-regulation of Scavenger Receptor Class B, Type 1. Gastroenterology, 150(3), 650-658. https://doi.org/10.1053/j.gastro.2015.11.015

Briand, O, Touche, V, Colin, S, Brufau, G, Davalos, A, Schonewille, M, Bovenga, F, Carrière, V, De Boer, JF, Dugardin, C, Riveau, B, Clavey, V, Tailleux, A, Moschetta, A, Lasunción, MA, Groen, AK, Staels, B & Lestavel, S 2016, 'Liver X Receptor Regulates Triglyceride Absorption Through Intestinal Down-regulation of Scavenger Receptor Class B, Type 1', Gastroenterology, vol. 150, no. 3, pp. 650-658. https://doi.org/10.1053/j.gastro.2015.11.015

@article{b275105e11f449f0bd98c54328893fee,

title = "Liver X Receptor Regulates Triglyceride Absorption Through Intestinal Down-regulation of Scavenger Receptor Class B, Type 1",

abstract = "Background & Aims Reducing postprandial triglyceridemia may be a promising strategy to lower the risk of cardiovascular disorders associated with obesity and type 2 diabetes. In enterocytes, scavenger receptor class B, type 1 (SR-B1, encoded by SCARB1) mediates lipid-micelle sensing to promote assembly and secretion of chylomicrons. The nuclear receptor subfamily 1, group H, members 2 and 3 (also known as liver X receptors [LXRs]) regulate genes involved in cholesterol and fatty acid metabolism. We aimed to determine whether intestinal LXRs regulate triglyceride absorption. Methods C57BL/6J mice were either fed a cholesterol-enriched diet or given synthetic LXR agonists (GW3965 or T0901317). We measured the production of chylomicrons and localized SR-B1 by immunohistochemistry. Mechanisms of postprandial triglyceridemia and SR-B1 regulation were studied in Caco-2/TC7 cells incubated with LXR agonists. Results In mice and in the Caco-2/TC7 cell line, LXR agonists caused localization of intestinal SR-B1 from apical membranes to intracellular organelles and reduced chylomicron secretion. In Caco-2/TC7 cells, LXR agonists reduced SR-B1-dependent lipidic-micelle-induced Erk phosphorylation. LXR agonists also reduced intracellular trafficking of the apical apolipoprotein B pool toward secretory compartments. LXR reduced levels of SR-B1 in Caco-2/TC7 cells via a post-transcriptional mechanism that involves microRNAs. Conclusion In Caco-2/TC7 cells and mice, intestinal activation of LXR reduces the production of chylomicrons by a mechanism dependent on the apical localization of SR-B1.",

keywords = "Fat Absorption, Hypertriglyceridemia, Lipid-Sensing, Triglyceride-Rich Lipoproteins",

author = "Olivier Briand and V{\'e}ronique Touche and Sophie Colin and Gemma Brufau and Alberto Davalos and Marleen Schonewille and Fabiola Bovenga and V{\'e}ronique Carri{\`e}re and {De Boer}, {Jan Freark} and Camille Dugardin and B{\'e}atrice Riveau and V{\'e}ronique Clavey and Anne Tailleux and Antonio Moschetta and Lasunci{\'o}n, {Miguel A.} and Groen, {Albert K.} and Bart Staels and Sophie Lestavel",

note = "Funding Information: Funding Supported by grants from the European Genomic Institute for Diabetes (ANR-10-LABX-46; and the European Commission, Fondation Leducq Transatlantic Networks of Excellence in Cardiovascular Research (10CVD04). Supported by the Instituto de Salud Carlos III (FIS, PI11/00315 to A.D.). B.S. is a member of and funded by the Institut Universitaire de France. Publisher Copyright: {\textcopyright} 2016 AGA Institute.",

year = "2016",

month = mar,

day = "1",

doi = "10.1053/j.gastro.2015.11.015",

language = "English (US)",

volume = "150",

pages = "650--658",

journal = "Gastroenterology",

issn = "0016-5085",

publisher = "W.B. Saunders Ltd",

number = "3",

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TY - JOUR

T1 - Liver X Receptor Regulates Triglyceride Absorption Through Intestinal Down-regulation of Scavenger Receptor Class B, Type 1

AU - Briand, Olivier

AU - Touche, Véronique

AU - Colin, Sophie

AU - Brufau, Gemma

AU - Davalos, Alberto

AU - Schonewille, Marleen

AU - Bovenga, Fabiola

AU - Carrière, Véronique

AU - De Boer, Jan Freark

AU - Dugardin, Camille

AU - Riveau, Béatrice

AU - Clavey, Véronique

AU - Tailleux, Anne

AU - Moschetta, Antonio

AU - Lasunción, Miguel A.

AU - Groen, Albert K.

AU - Staels, Bart

AU - Lestavel, Sophie

N1 - Funding Information: Funding Supported by grants from the European Genomic Institute for Diabetes (ANR-10-LABX-46; and the European Commission, Fondation Leducq Transatlantic Networks of Excellence in Cardiovascular Research (10CVD04). Supported by the Instituto de Salud Carlos III (FIS, PI11/00315 to A.D.). B.S. is a member of and funded by the Institut Universitaire de France. Publisher Copyright: © 2016 AGA Institute.

PY - 2016/3/1

Y1 - 2016/3/1

N2 - Background & Aims Reducing postprandial triglyceridemia may be a promising strategy to lower the risk of cardiovascular disorders associated with obesity and type 2 diabetes. In enterocytes, scavenger receptor class B, type 1 (SR-B1, encoded by SCARB1) mediates lipid-micelle sensing to promote assembly and secretion of chylomicrons. The nuclear receptor subfamily 1, group H, members 2 and 3 (also known as liver X receptors [LXRs]) regulate genes involved in cholesterol and fatty acid metabolism. We aimed to determine whether intestinal LXRs regulate triglyceride absorption. Methods C57BL/6J mice were either fed a cholesterol-enriched diet or given synthetic LXR agonists (GW3965 or T0901317). We measured the production of chylomicrons and localized SR-B1 by immunohistochemistry. Mechanisms of postprandial triglyceridemia and SR-B1 regulation were studied in Caco-2/TC7 cells incubated with LXR agonists. Results In mice and in the Caco-2/TC7 cell line, LXR agonists caused localization of intestinal SR-B1 from apical membranes to intracellular organelles and reduced chylomicron secretion. In Caco-2/TC7 cells, LXR agonists reduced SR-B1-dependent lipidic-micelle-induced Erk phosphorylation. LXR agonists also reduced intracellular trafficking of the apical apolipoprotein B pool toward secretory compartments. LXR reduced levels of SR-B1 in Caco-2/TC7 cells via a post-transcriptional mechanism that involves microRNAs. Conclusion In Caco-2/TC7 cells and mice, intestinal activation of LXR reduces the production of chylomicrons by a mechanism dependent on the apical localization of SR-B1.

AB - Background & Aims Reducing postprandial triglyceridemia may be a promising strategy to lower the risk of cardiovascular disorders associated with obesity and type 2 diabetes. In enterocytes, scavenger receptor class B, type 1 (SR-B1, encoded by SCARB1) mediates lipid-micelle sensing to promote assembly and secretion of chylomicrons. The nuclear receptor subfamily 1, group H, members 2 and 3 (also known as liver X receptors [LXRs]) regulate genes involved in cholesterol and fatty acid metabolism. We aimed to determine whether intestinal LXRs regulate triglyceride absorption. Methods C57BL/6J mice were either fed a cholesterol-enriched diet or given synthetic LXR agonists (GW3965 or T0901317). We measured the production of chylomicrons and localized SR-B1 by immunohistochemistry. Mechanisms of postprandial triglyceridemia and SR-B1 regulation were studied in Caco-2/TC7 cells incubated with LXR agonists. Results In mice and in the Caco-2/TC7 cell line, LXR agonists caused localization of intestinal SR-B1 from apical membranes to intracellular organelles and reduced chylomicron secretion. In Caco-2/TC7 cells, LXR agonists reduced SR-B1-dependent lipidic-micelle-induced Erk phosphorylation. LXR agonists also reduced intracellular trafficking of the apical apolipoprotein B pool toward secretory compartments. LXR reduced levels of SR-B1 in Caco-2/TC7 cells via a post-transcriptional mechanism that involves microRNAs. Conclusion In Caco-2/TC7 cells and mice, intestinal activation of LXR reduces the production of chylomicrons by a mechanism dependent on the apical localization of SR-B1.

KW - Fat Absorption

KW - Hypertriglyceridemia

KW - Lipid-Sensing

KW - Triglyceride-Rich Lipoproteins

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Liver X Receptor Regulates Triglyceride Absorption Through Intestinal Down-regulation of Scavenger Receptor Class B, Type 1

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