2Intestinal 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 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, but have increased postprandial LDL cholesterol, total free fatty acids (FA), palmitoleic acid, and palmitic acid. The increase in circulating fatty acids in HFD CAV1IEC-KO mice are mirrored by decreased hepatic fatty acids suggesting a non-cell autonomous role in IEC CAV1 in promoting hepatic fatty acid 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 FA and LDL cholesterol, since high levels are associated with development of type II diabetes and cardiovascular disease.