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

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• 作者：Olivier Briand¹ ; Vé ; ronique Touche¹ ; Sophie Colin¹ ; Gemma Brufau² ; Alberto Davalos³ ; Marleen Schonewille² ; Fabiola Bovenga⁴ ; Vé ; ronique Carriè ; re⁶ ; ⁷ ; ⁸ ; Jan Freark de Boer² ; Camille Dugardin¹ ; Bé ; atrice Riveau⁵ ; ⁶ ; ⁷ ; Vé ; ronique Clavey¹ ; Anne Tailleux¹ ; Antonio Moschetta⁴ ; Miguel A. Lasunció ; n⁸ ; ⁹ ; Albert K. Groen² ; Bart Staels¹ ; ^{bart.staels@pasteur-lille.fr" class="auth_mail" title="E-mail the corresponding author} ; Sophie Lestavel¹
• 关键词：Hypertriglyceridemia ; Lipid-Sensing ; Fat Absorption ; Triglyceride-Rich Lipoproteins
• 刊名：Gastroenterology
• 出版年：2016
• 出版时间：March 2016
• 年：2016
• 卷：150
• 期：3
• 页码：650-658
• 全文大小：1363 K

文摘

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.