Genetic Regulation of Intestinal Lipid Transport and Metabolism

Intestinal lipid transport is coordinated through pathways that facilitate uptake and metabolic channeling of fatty acids, monoglycerides, lipovitamins, and sterols into complex lipid for temporary storage and systemic delivery. The key rate limiting steps include transport across the brush-border membrane, vectorial delivery within apical cytoplasmic compartments to the endoplasmic reticulum (ER), and initiation of lipoprotein biogenesis. Within the ER, primordial lipid droplet particles are remodeled and undergo maturation through the Golgi profiles and nascent intracellular chylomicrons are eventually secreted into the pericellular basolateral spaces and lymphatic fenestrae. We review current understanding of intestinal lipoprotein biogenesis and the role of dominant and modifier genes in coordinating chylomicron assembly and secretion. We further discuss developments in understanding how intestinal lipid (including fatty acid and cholesterol) transport is disrupted in selected genetic disorders, with new insights into critical pathways, their physiologic regulation, and potential utility as pharmacologic targets.