Regulation of intestinal lipid metabolism: current concepts and relevance to disease

Lipids entering the gastrointestinal tract include dietary lipids (triacylglycerols, cholesteryl esters and phospholipids) and endogenous lipids from bile (phospholipids and cholesterol) and from shed intestinal epithelial cells (enterocytes). Here, we comprehensively review the digestion, uptake and intracellular re-synthesis of intestinal lipids as well as their packaging into pre-chylomicrons in the endoplasmic reticulum, their modification in the Golgi apparatus and the exocytosis of the chylomicrons into the lamina propria and subsequently to lymph. We also discuss other fates of intestinal lipids, including intestinal HDL and VLDL secretion, cytosolic lipid droplets and fatty acid oxidation. In addition, we highlight the applicability of these findings to human disease and the development of therapeutics targeting lipid metabolism. Finally, we explore the emerging role of the gut microbiota in modulating intestinal lipid metabolism and outline key questions for future research. The small intestine is a key site for the absorption of nutrients, including lipids. In this Review, the physiology and biochemistry of intestinal fat absorption during health and disease is discussed, including insights into enterocyte biology and clinical disorders of intestinal fat absorption. Key points Dietary lipids are digested and are taken up by enterocytes for re-esterification and packaging into pre-chylomicrons in the endoplasmic reticulum, trafficked to the Golgi and then secreted for transport in the lymphatic system. Specific proteins and enzymes are involved in this complex process; when deficient, human diseases characterized by defective lipid and fat-soluble vitamin absorption, such as abetalipoproteinaemia and chylomicron storage disease, occur. Cytoplasmic lipid droplets are multiprotein-coated structures that serve as dynamic triacylglycerol storage pools in the enterocyte and are involved in several aspects of enterocyte lipid metabolism. Pharmacotherapy targeted to specific proteins and/or molecules involved in the absorptive process, such as luminal lipases, bile acids, NPC1L1, MGAT2, DGAT1 and MTP, could be used to treat diet-induced obesity and its associated complications. Studies have suggested that the gut microbiome in the small intestine has a role in regulating host metabolism and the response to dietary lipids.