Regulation of Chylomicron Secretion: Focus on Post-Assembly Mechanisms

Abstract

Rapid and efficient digestion and absorption of dietary triglycerides and other lipids by the intestine, the packaging of those lipids into lipoprotein chylomicron (CM) particles, and their secretion via the lymphatic duct into the blood circulation are essential in maintaining whole-body lipid and energy homeostasis. Biosynthesis and assembly of CMs in enterocytes is a complex multistep process that is subject to regulation by intracellular signaling pathways as well as by hormones, nutrients, and neural factors extrinsic to the enterocyte. Dysregulation of this process has implications for health and disease, contributing to dyslipidemia and a potentially increased risk of atherosclerotic cardiovascular disease. There is increasing recognition that, besides intracellular regulation of CM assembly and secretion, regulation of postassembly pathways also plays important roles in CM secretion. This review examines recent advances in our understanding of the regulation of CM secretion in relation to mobilization of intestinal lipid stores, drawing particular attention to post-assembly regulatory mechanisms, including intracellular trafficking of triglycerides in enterocytes, CM mobilization from the lamina propria, and regulated transport of CM by intestinal lymphatics.

Keywords: Chylomicron; Intestine; Lymphatics; Triglycerides.

Figure 1

Triglyceride trafficking, storage, and mobilization in the small intestine. TGs are present in various pools in intracellular and extracellular spaces within the intestinal structure. Digestion products of dietary TGs are absorbed at the brush border across the apical membrane of the enterocyte. TG resynthesis through the MGAT (majority) or the G3P pathways occurs in the outer ER membrane. Lipid droplets formed in the ER membrane are packaged into pre-CMs that are transported in PCTVs to the Golgi for further processing. Mature CM particles exit the basolateral membrane via exocytosis of secretory vesicles. Lipid droplets in the ER membrane also may bud off to form CLDs that are recruited for CM synthesis during the interprandial period or are degraded in the autophagosome (APS). A putative, apical/subapical pool of lipid-poor apoB48 may be recruited for rapid CM secretion and replenished by lipid supply during the feeding–fasting cycle. Secreted CM particles move through the lamina propria, enter the lacteals, and are actively transported in lymphatic vessels of increasing size before being released into circulation. CM entry into lacteals occurs mainly through size exclusion, but certain prerequisites such as particular CM composition also play a role. SMC around the lacteal and larger lymphatic vessels, which may be modulated by neural inputs, VEGF-C, and other regulators, actively regulates lymph flow and CM transport to the circulation. CoA, coenzyme A; DG, diacylglycerol.