Cytosolic

BULK SOLUTION DIFFUSION BAftftlER COMPARTMENT IN OVERLYING OF INTESTINAL

INTESTINAL LUMEN MICROVILLI EPITHELIAL CELL

Figure 4 Diagrammatic representation of the effect of bile salt micelles (or vesicles) in overcoming the diffusion barrier resistance by the unstirred water layer. In the absence of bile acids, individual lipid molecules must diffuse across the barriers overlying the microvillus border of the intestinal epithelial cells (arrow 1). Hence, uptake of these molecules is largely diffusion limited. In the presence of bile acids (arrow 2), large amounts of these lipid molecules are delivered directly to the aqueous-membrane interface so that the rate of uptake is greatly enhanced. Source: From Ref. 97.

Figure 4 Diagrammatic representation of the effect of bile salt micelles (or vesicles) in overcoming the diffusion barrier resistance by the unstirred water layer. In the absence of bile acids, individual lipid molecules must diffuse across the barriers overlying the microvillus border of the intestinal epithelial cells (arrow 1). Hence, uptake of these molecules is largely diffusion limited. In the presence of bile acids (arrow 2), large amounts of these lipid molecules are delivered directly to the aqueous-membrane interface so that the rate of uptake is greatly enhanced. Source: From Ref. 97.

and MG in aqueous media is extremely low, very few of these molecules are able to penetrate the UWL unaided (Fig. 4, arrow 1). Micellar solubilization, by greatly increasing the aqueous solubility of FA and MG, promotes the diffusion of these substances across the UWL allowing contact with the brush border membrane and subsequent absorption by the enterocytes (Fig. 4, arrow 2).

Although bile salt mixed-micellar solubilization plays a central role in lipid absorption, the mechanism(s) by which bile salts facilitate the uptake of lipid soluble molecules and drugs by the small intestine may extend beyond their detergent properties. For instance, several investigators have reported that trihydroxy bile acids are more effective in promoting cholesterol absorption than dihydroxy bile acids; however, the degree of solubilization was not measured in these experiments (105-107). Watt and Simmonds (107) elegantly demonstrated the importance of micellar solubilization by bile salts in the uptake of cholesterol by the small intestine by showing that a linear relationship exists between the amount of absorbed cholesterol and the micellar cholesterol concentration. Their study demonstrated that cholesterol uptake by enterocytes is dependent on the specific planar structure of the bile acid by using Pluronic F-68, a nonionic surfactant with different molecular geometry that promotes the micellar solubilization of cholesterol (but not its uptake by enterocytes). A particularly important finding in this study was that the degree of nonspecific binding of cholesterol to silicone tubing was similar for micellar solutions of cholesterol, solubilized with either Pluronic F-68 or bile acids. This suggests that intestinal cholesterol absorption is an active process, possibly mediated by a transporter, and supports an earlier finding by Sylven (111), that both cholesterol and beta-sitosterol (plant sterol) are present in the human diet but that cholesterol, unlike beta-sitosterol, is well absorbed by the small intestine. Sylven found that the ability of the small intestine to discriminate between cholesterol and beta-sitosterol absorption is energy-dependent and compromised by deprivation of blood supply (111). The possibility that lipid transporters are present at the brush border membrane is further suggested in patients with beta-sitosterolemia, a condition where the intestine fails to discriminate between cholesterol and beta-sitosterol (112-114). This topic will be discussed in detail later in this chapter.

The dependence of cholesterol absorption on bile salt structure is further illustrated by the fact that chenodeoxycholyl taurine (CDC-tau), which is a better micellar solubilizer of cholesterol than cholyl taurine (C-tau), results in poorer cholesterol uptake than C-tau (108-110). Despite the knowledge gained from these studies and others, the manner in which bile salt structure affects its ability to promote the absorption of cholesterol and other lipid soluble drugs and xenobiotics is far from being clear.

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