Glucagon-like Peptide-2 Acutely Enhances Chylomicron Secretion in Humans Without Mobilizing Cytoplasmic Lipid Droplets.

Abstract

A portion of ingested fats are retained in the intestine for many hours before they are mobilized and secreted in chylomicron (CM) particles. Factors such as glucagon-like peptide-2 (GLP-2) and glucose can mobilize these stored intestinal lipids and enhance CM secretion. We have recently demonstrated in rodents that GLP-2 acutely enhances CM secretion by mechanisms that do not involve the canonical CM synthetic assembly and secretory pathways. To further investigate the mechanism of GLP-2's potent intestinal lipid mobilizing effect, we examined intracellular cytoplasmic lipid droplets (CLDs) in intestinal biopsies of humans administered GLP-2 or placebo. A single dose of placebo or GLP-2 was administered subcutaneously 5 hours after ingesting a high-fat bolus. In 1 subset of participants, plasma samples were collected to quantify lipid and lipoprotein concentrations for 3 hours after placebo or GLP-2. In another subset, a duodenal biopsy was obtained 1-hour after placebo or GLP-2 administration for transmission electron microscopy and proteomic analysis. GLP-2 significantly increased plasma triglycerides by 46% (P = 0.009), mainly in CM-sized particles by 133% (P = 0.003), without reducing duodenal CLD size or number. Several proteins of interest were identified that require further investigation to elucidate their potential role in GLP-2-mediated CM secretion. Unlike glucose that mobilizes enterocyte CLDs and enhances CM secretion, GLP-2 acutely increased plasma CMs without significant mobilization of CLDs, supporting our previous findings that GLP-2 does not act directly on enterocytes to enhance CM secretion and most likely mobilizes secreted CMs in the lamina propria and lymphatics.