An Updated Perspective on the Dual-Track Model of Enterocyte Fat Metabolism

The small intestinal epithelium has classically been envisioned as a conduit for nutrient absorption, but appreciation is growing for a larger and more dynamic role for enterocytes in lipid metabolism. Considerable gaps remain in our knowledge of this physiology, but it appears that the enterocyte's structural polarization dictates its behavior in fat partitioning, treating fat differently based on its absorption across the apical versus the basolateral membrane. In this review, we synthesize existing data and thought on this dual-track model of enterocyte fat metabolism through the lens of human integrative physiology. The apical track includes the canonical pathway of dietary lipid absorption across the apical brush-border membrane, leading to packaging and secretion of those lipids as chylomicrons. However, this track also reserves a portion of dietary lipid within cytoplasmic lipid droplets for later uses, including the "second-meal effect," which remains poorly understood. At the same time, the enterocyte takes up circulating fats across the basolateral membrane by mechanisms that may include receptor-mediated import of triglyceride-rich lipoproteins or their remnants, local hydrolysis and internalization of free fatty acids, or enterocyte de novo lipogenesis using basolaterally absorbed substrates. The ultimate destinations of basolateral-track fat may include fatty acid oxidation, structural lipid synthesis, storage in cytoplasmic lipid droplets, or ultimate resecretion, although the regulation and purposes of this basolateral track remain mysterious. We propose that the enterocyte integrates lipid flux along both of these tracks in order to calibrate its overall program of lipid metabolism.