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.