A relatively new approach to treating hypercholesterolemia focuses on inhibiting the absorption of cholesterol in the small intestine, whether it comes from the diet or bile. Ezetimibe is a drug that specifically blocks the cellular uptake of cholesterol by inhibiting the activity of the NPC1L1 protein expressed in the apical membrane of enterocytes. When used alongside other drugs aimed at countering atherosclerosis, it can interrupt the enterohepatic circulation and prevent the absorption of dietary cholesterol. Clinical studies suggest that ezetimibe may synergistically improve the efficacy of other strategies designed to reduce low-density lipoprotein cholesterol levels in individuals at risk for cardiovascular disease, such as statin drugs.

In terms of their fate after absorption into the enterocyte, lipids differ from carbohydrates and proteins. Monosaccharides and amino acids leave the enterocyte in molecular form and enter the portal circulation, while the products of lipolysis are reesterified within the enterocyte to form triglycerides, phospholipids, and cholesterol esters. These metabolic events occur in the smooth endoplasmic reticulum. Simultaneously, the enterocyte synthesizes a series of proteins called apolipoproteins in the rough endoplasmic reticulum. These proteins combine with the resynthesized lipids to create chylomicrons, which consist of a lipid core primarily composed of triglycerides, along with smaller amounts of cholesterol, phospholipids, and fat-soluble vitamin esters. The apolipoproteins coat the chylomicrons. Through exocytosis, the chylomicrons are then released from the enterocyte. However, upon entering the lamina propria, they are too large (approximately 750–5000 Å in diameter) to pass through the intercellular spaces of the mucosal capillaries. Instead, they are taken up into the lymphatics in the lamina propria, bypassing the portal circulation and the liver during their first pass. Eventually, the chylomicrons in the lymph enter the bloodstream via the thoracic duct and act as vehicles for transporting lipids to other organs for cellular utilization. The only exception to this chylomicron-mediated transport is for medium-chain fatty acids. These acids are relatively soluble in water and can permeate enterocyte tight junctions significantly, allowing them to bypass the intracellular processing steps mentioned earlier and not be packaged into chylomicrons. Consequently, they enter the portal circulation more readily and become readily available to other tissues. A diet rich in medium-chain triglycerides may be particularly beneficial for patients with inadequate bile acid pools.
Arelativelynewtreatmentforhypercholesterolemiatargetsabsorptionofcholesterol,eitherderivedfromthedietorinbile,acrossthesmallintestinalepithelium.EzetimibeisadrugthatspecificallyblockscellularuptakeofcholesterolbyinhibitingtheactivityoftheNPC1L1proteinexpressedintheapicalmembraneofenterocytes.Inconjunctionwithotherdrugsdesignedtocounteratherosclerosis,thismaybeausefuladjunctinthatitcaninterrupttheenterohepaticcirculationaswellaspreventabsorptionofdietarycholesterol.Clinicalstudiessuggestthatezetimibemaysynergisticallyimprovetheefficacyofotherstrategiesdesignedtoreducecirculatinglevelsoflow-densitylipoproteincholesterolinthoseatriskforcardiovasculardisease,suchastheuseofstatindrugs.
Lipids also differ from carbohydrates and proteins in terms of their fate after absorption into the enterocyte. Unlike monosaccharides and amino acids, which leave the enterocyte in molecular form and enter the portal circulation, the products of lipolysis are reesterified in the enterocyte to form triglycerides, phospholipids, and cholesterol esters. These metabolic events take place in the smooth endoplasmic reticulum. Concurrently the enterocyte synthesizes a series of proteins known as apolipoproteins in the rough endoplasmic reticulum. These proteins are then combined with the resynthesized lipids to form a structure known as a chylomicron, which consists of a lipid core (predominantly triglyceride with much less cholesterol, phospholipid, and fat-soluble vitamin esters) coated by the apolipoproteins. The chylomicrons are then exported from the enterocyte by a process of exocytosis. However, on entering the lamina propria, they are too large (≈750–5000 Å in diameter) to permeate through the intercellular spaces of the mucosal capillaries. Instead they are taken up into lymphatics in the lamina propria and therefore bypass the portal circulation and, at least for their first pass, the liver. Eventually, chylomicrons in the lymph enter the bloodstream via the thoracic duct and then serve as the vehicle to transport lipids around the body for use by cells in other organs. The only exception to this chylomicron-mediated transport is for medium-chain fatty acids. These acids are relatively water soluble and can also permeate enterocyte tight junctions appreciably, which means that they bypass the intracellular processing steps described earlier and are not packaged into chylomicrons. They therefore enter the portal circulation and are more readily available to other tissues. A diet rich in medium-chain triglycerides may be of particular benefit in patients with inadequate bile acid pools.