The Intestinal Absorption of Biliary and Dietary Cholesterol as a Drug Target for Lowering the Plasma Cholesterol Level

Stephen D. Turley, PhD, John M. Dietschy, MD


Prev Cardiol. 2003;6(1) 

In This Article

Intestinal Cholesterol Absorption and Its Regulation

Cholesterol absorption occurs primarily in the duodenum and proximal jejunum at levels of efficiency that vary greatly among different individuals.[13,14] The absorption process is largely specific for cholesterol because plant sterols, although structurally similar to cholesterol, are generally absorbed either poorly or not at all.[15] In humans consuming a typical Western diet, only about one quarter of the cholesterol entering the lumen of the small bowel is from the diet; the bulk of cholesterol in the lumen comes directly from the bile and cells sloughed from the intestinal epithelium.[8] There are two main phases of cholesterol absorption.[16,17] The first takes place in the lumen and involves digestion and hydrolysis of dietary lipids followed by solubilization of cholesterol in mixed micelles containing bile acid and phospholipids. This solubilization facilitates the movement of cholesterol from the bulk phase of the lumen to the surface of the enterocyte. In the second phase, cholesterol crosses the mucosal cell membrane by simple diffusion, and probably by facilitated diffusion as well. Thus far, a specific cholesterol transporter in the microvillus membrane of the enterocyte has not been identified.[18,19] Within the cell the cholesterol is re-esterified and incorporated into apolipoprotein B-containing nascent lipoproteins that are secreted into the lymph.

Currently, it remains uncertain which step in the absorption process is rate-limiting. It is nevertheless known that the physicochemical environment within the lumen plays a major role in dictating the efficiency of cholesterol absorption. Thus, changes in bile acid pool size and composition, as well as in the amount and species of phospholipid in the lumen, can each profoundly affect the amount of chylomicron cholesterol that ultimately enters the lymph.[17] In addition to the question of whether cholesterol absorption might be regulated by a transporter in the mucosal cell membrane, there is also the possibility that proteins like adenosine triphosphate-binding cassette (ABC): ABCA1, ABCG5, and ABCG8, which promote sterol efflux from cells, might also play a critical role in dictating the amount of cholesterol that reaches the lymph from the intestinal lumen.[20,21,22] Irrespective of what mechanisms are ultimately found to control cholesterol absorption, it is clear that any new strategy designed to maximize LDL-C lowering ideally should include an agent(s) that blocks the re-entry of biliary cholesterol, as well as the uptake of dietary cholesterol into the body pools.


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