Intestinal epithelial cell caveolin 1 regulates fatty acid and lipoprotein cholesterol plasma levels.

Jessica P Otis,Meng-Chieh Shen,Steven A Farber,Jennifer L Anderson,Vanessa Quinlivan

doi:10.1242/dmm.027300

Abstract

ABSTRACTCaveolae 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-KO mice 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-KO mice 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.

Highlights

Caveolae are flask-shaped pits, 50 to 100 nm in diameter, which form in lipid-rich plasma membrane (PM) regions of most vertebrate cells (Parton and Simons, 2007)
Caveolae-mediated endocytosis occurs only on the basolateral side of enterocytes The asymmetric PM localization of zebrafish enterocyte Cav1 suggests that caveolae-specific endocytosis occurs between the intestinal epithelia and submucosa, but not the intestinal lumen
Previous work had identified functional roles of adipocyte and endothelial caveolin 1 (CAV1) in susceptibility to diet-induced obesity (Razani et al, 2002), insulin resistance (Cohen et al, 2003) and atherosclerosis (Frank et al, 2004). We expanded upon these findings by using zebrafish larvae to visualize the localization of enterocyte Cav1 and caveolar endocytosis, and a knockout mouse model to identify a role for CAV1 in the intestinal epithelia in the regulation of plasma fatty acids (FAs) and low-density lipoprotein (LDL) cholesterol, lipids that contribute to the development of several metabolic diseases

Summary

Introduction

Caveolae are flask-shaped pits, 50 to 100 nm in diameter, which form in lipid-rich plasma membrane (PM) regions of most vertebrate cells (Parton and Simons, 2007). A threshold level of membrane cholesterol is required for caveolae to form (Rothberg et al, 1992) and CAV1 can directly bind cholesterol (Murata et al, 1995) and fatty acids (FAs) (Trigatti et al, 1999). Recognized for their endocytic function, caveolae regulate cell-signaling pathways, internalization of cell-surface receptors and ligands, cell adhesion molecule expression, exocytosis, and transcytosis of caveolae cargos (Parton and Simons, 2007). The plasma lipid and body mass changes in CAV1KO mice have been proposed to result from a variety of mechanisms including altered lipid droplet architecture, reduced adipocyte lipid droplet formation (Cohen et al, 2004), and impaired adipocyte metabolic flexibility (Asterholm et al, 2012), whereas protection from atherosclerosis is likely a result of decreased endothelial adhesion molecule expression

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