title: Intestinal epithelial cell caveolin 1 regulates fatty acid and lipoprotein cholesterol plasma levels.
abstract: Caveolae and their structural protein caveolin 1 (CAV1) have roles in cellular lipid processing and systemic lipid metabolism. Global deletion of CAV1 in mice results in insulin resistance and increases in atherogenic plasma lipids and cholesterol, but protects from diet-induced obesity and atherosclerosis. Despite the fundamental role of the intestinal epithelia in the regulation of dietary lipid processing and metabolism, the contributions of CAV1 to lipid metabolism in this tissue have never been directly investigated. In this study the cellular dynamics of intestinal Cav1 were visualized in zebrafish and the metabolic contributions of CAV1 were determined with mice lacking CAV1 in intestinal epithelial cells (CAV1IEC-KO). Live imaging of Cav1-GFP and fluorescently labeled caveolae cargos shows localization to the basolateral and lateral enterocyte plasma membrane (PM), suggesting Cav1 mediates transport between enterocytes and the submucosa. CAV1IEC-KOmice are protected from the elevation in circulating fasted low-density lipoprotein (LDL) cholesterol associated with a high-fat diet (HFD), but have increased postprandial LDL cholesterol, total free fatty acids (FFAs), palmitoleic acid, and palmitic acid. The increase in circulating FAs in HFD CAV1IEC-KOmice is mirrored by decreased hepatic FAs, suggesting a non-cell-autonomous role for intestinal epithelial cell CAV1 in promoting hepatic FA storage. In conclusion, CAV1 regulates circulating LDL cholesterol and several FA species via the basolateral PM of enterocytes. These results point to intestinal epithelial cell CAV1 as a potential therapeutic target to lower circulating FFAs and LDL cholesterol, as high levels are associated with development of type II diabetes and cardiovascular disease.
authors.affiliation: Carnegie Institution for Science, Department of Embryology, Baltimore, MD 21218, USA.
authors.forename: Jessica P
authors.identifier: 0000-0003-3562-350X
authors.initials: JP
authors.lastname: Otis
authors.affiliation: Carnegie Institution for Science, Department of Embryology, Baltimore, MD 21218, USA.
authors.forename: Meng-Chieh
authors.initials: MC
authors.lastname: Shen
authors.affiliation: Carnegie Institution for Science, Department of Embryology, Baltimore, MD 21218, USA.|Johns Hopkins University, Department of Biology, Baltimore, MD 21218, USA.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Quinlivan
authors.affiliation: Carnegie Institution for Science, Department of Embryology, Baltimore, MD 21218, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Anderson
authors.affiliation: Carnegie Institution for Science, Department of Embryology, Baltimore, MD 21218, USA farber@ciwemb.edu.|Johns Hopkins University, Department of Biology, Baltimore, MD 21218, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Farber
mesh_terms: D000818:Animals; D001835:Body Weight; D021941:Caveolae / Q000378:metabolism / Q000648:ultrastructure; D051242:Caveolin 1 / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002784:Cholesterol / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D059305:Diet, High-Fat; D004705:Endocytosis; D020895:Enterocytes / Q000378:metabolism* / Q000648:ultrastructure; D005227:Fatty Acids / Q000097:blood*; D005456:Fluorescent Dyes / Q000378:metabolism; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism; D008074:Lipoproteins / Q000097:blood*; D008297:Male; D055432:Metabolomics; D018345:Mice, Knockout; D014280:Triglycerides / Q000097:blood; D015027:Zebrafish / Q000378:metabolism
chemical_list: D051242:Caveolin 1; D008078:Cholesterol, LDL; D005227:Fatty Acids; D005456:Fluorescent Dyes; D008074:Lipoproteins; D014280:Triglycerides; C030104:lipoprotein cholesterol; D002784:Cholesterol; D005947:Glucose
keywords: Caveolae; Caveolin 1; Free fatty acids; Knockout mice; LDL cholesterol; Zebrafish