Exogenous Cholesterol Transport

Cholesterol is absorbed in the unesterified state, whereas the cholesterol secreted into the lymph is 70-80% esterified. This esterification process generates a concentration gradient of free cholesterol within the mucosal cell that may facilitate absorption rates. Cholesterol is esterified in intestinal mucosal cells by acyl-coenzyme A:cholesterol acyl-transferase-2 to form cholesteryl esters, which are secreted from the basolateral surface of the entero-cyte as part of the chylomicrons. At this stage, it is assumed that cholesterol molecules from exogenous and endogenous sources are indistinguishable and have similar effects on endogenous cholesterol and lipoprotein metabolism. Chylomicrons are large particles (>70 nm in diameter) composed mainly of triacylglycerols (95% by weight) and contain 37% cholesterol by weight, with the esterified cholesterol localized in the hydrophobic core and the free cholesterol primarily in the hydrophilic outer layer. The data indicate that the amount of dietary cholesterol consumed has little effect on the cholesterol content of chylomicrons. The chylomicrons are released from the intestinal cells, enter the lymphatic system, and are transported via the lymphatics (thoracic duct) to the bloodstream. Since chylomicrons are too large to pass through the capillaries, this is the only mechanism by which they can enter the bloodstream.

In the plasma compartment, the chylomicrons pick up a number of apolipoproteins, which are required for intravascular metabolism of the particles. The initial metabolism of chylomicrons involves hydrolysis of the associated triacylglycerols by endothelial cell lipoprotein lipase (LPL) located in adipose, muscle, and heart tissues, which results in production of chylomicron remnants. The chylomicron remnants, depleted of triacylglycerol and enriched with choles-teryl ester, are taken up by the liver via the LDL receptor-related protein (LRP). The ligand for hepatic uptake of the chylomicron remnant appears from various transgenic mouse studies to be the apo-E moiety of the particle. The clearance of chylomicrons from the bloodstream is rapid, with particles having a half-life of less than 1 h. The liver cannot take up native chylomicrons but rather takes up the chylomi-cron remnant, which has lost approximately 90% of its triacylglycerol content and become relatively enriched in free and esterified cholesterol through the actions of the plasma cholesteryl ester transfer protein (CETP), which transfers cholesteryl ester from high-density lipoprotein (HDL) to the apo-B-containing lipoproteins.

The chylomicron remnants taken up by the liver are subjected to lysosomal hydrolysis, resulting in the release of the absorbed dietary and biliary cholesterol into the hepatocyte as free cholesterol. The influx of cholesterol contained in the chylomicron remnant has the ability to affect a number of regulatory sites of hepatic cholesterol metabolism that function to maintain cholesterol homeostasis in the liver. The liver has four primary fates for the newly delivered cholesterol: catabolism to bile acids, secretion as biliary cholesterol, storage in lipid droplets as cholesteryl ester, or incorporation into very low-density lipoprotein (VLDL) for secretion from the liver.

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