Lipidomic analysis of postprandial mesenteric lymph from wild type and Dennd5b knockout mice.

Chylomicrons are intestine-derived lipoproteins that transport dietary lipids from the intestine to the systemic circulation. Although the composition of chylomicrons may influence their peripheral metabolism and biological functions, the lipid composition of newly secreted chylomicrons remains incompletely characterized. In this study, we combined a conscious mesenteric lymph fistula model with mass spectrometry-based lipidomics to characterize changes in the intestinal lymph lipidome following duodenal lipid administration in wild type and Dennd5b-deficient mice, a model of impaired intestinal chylomicron secretion. In wild type mice, lipid administration significantly increased lymphatic triglyceride output and altered the abundance of multiple lipid species, including glycerolipids, glycerophospholipids, and sphingolipids. Notably, ceramides and hexosylceramides exhibited disproportionate increases relative to their abundance in the administered lipid. In contrast, Dennd5b-deficient mice exhibited a near-complete blunting of the postprandial lymphatic lipidomic response, with markedly attenuated export across multiple lipid classes. Genotype-dependent differences were also evident in baseline lymph, indicating that Dennd5b influences lymphatic lipid composition under both basal and postprandial conditions. Together, these findings demonstrate that the physiological impact of Dennd5b deficiency on intestinal lipid trafficking extends well beyond triglycerides, underscoring an essential role for Dennd5b-dependent chylomicron secretion in the coordinated lymphatic export of dietary and endogenous lipids.