It has been generally accepted that FA and MG are absorbed by enterocytes via passive diffusion (124,125). This hypothesis was first challenged by Chow and
Hollander, who demonstrated that linoleate uptake by the small intestine is concentration-dependent, occuring via a carrier-mediated process at low concentration but predominantly by passive diffusion at high concentrations (127). Similar concentration-dependent absorption kinetics were found to apply to the intestinal absorption of the fat-soluble vitamin A, whereas the intestinal uptake of vitamins D and E and carotene occur by strictly passive processes (128).
Studies by Stremmel (126,129) suggested the existence of an intestinal brush border membrane FA-binding protein (FABP) that plays an apparent role in the uptake of FA by enterocytes. This FABP, which is predominantly localized in the apical and lateral areas of the villus membrane in the regions of the tight junction and crypt, is also capable of transporting cholesterol, but not CE, and it was shown that pretreatment of a jejunal loop with an anti-FABP antibody significantly reduced cholesterol uptake (129). Consequently, this FABP appears to be a plausible candidate as a transporter for not only cholesterol, but a whole array of lipophilic molecules, including drugs. This hypothesis have been challenged for two reasons: firstly, this transporter was subsequently demonstrated to be similar to mitochondrial glutamic oxaloacetic transaminase, which is not involved in lipid absorption (130); secondly, crypt cells, which are not involved in fat absorption, express this FABP.
More recent work has confirmed the presence of FA transporters in the intestinal brush border membrane, the expression of which appears to be the highest in the jejunum, followed by the duodenum and the ileum. Furthermore, a diet rich in long-chain, but not medium-chain, FAs results in increased transporter expression (144). Interested readers are referred to a review on this subject by Abumrad et al. (145).
Other lipid-binding proteins have been identified, including GP330 (also called megalin), CD36, SR-BI, caveolin, and more recently, the FATP4 (131). GP330 is a member of the low-density lipoprotein receptor gene family and is an endocytic receptor expressed in many absorptive epithelia, including the kidney proximal tubules, Type II pneumocytes, mammary epithelium, and thyroid follicular cells (132). It has been demonstrated that GP330 is involved in the renal uptake of polybasic drugs (132-134), vitamin B12 (134), cholesterol carrying lipoproteins (135), albumin (136), and proteases (133). Whether GP330 is expressed in the intestine is still uncertain (132).
Other potential FA transporters have been identified. Schaffer and Lodish (146) cloned a long-chain FA in adipocytes. Stahl et al. (131,147) identified the presence of FATP4, a member of the large family of FA transport proteins, in the small intestine. This finding was initially confirmed by Hermann et al. (148) who subsequently found that both FATP1 and FATP4 to be constituents of acyl-CoA synthetase, with substrate specificity for very long-chain FA (149). Caveolin, the first reported protein associated with caveolae, is another protein that binds cholesterol (150). Caveolae are nonclathrin-coated invaginations present on the surface of cells and are enriched with glycolipids (151), cholesterol (152), glycosyl-phosphatidylinositol-linked proteins (153), and other proteins involved in potocytosis (154). It is currently unknown if caveolin plays a role in the intestinal absorption of cholesterol, FAs, or lipid soluble drugs.
Several studies have reported that cholesterol absorption by the small intestine is regulated by the adenosine triphosphate (ATP)-binding casette-1 (ABC-1), a reverse cholesterol transporter (155). If, indeed, ABC transporters are reverse cholesterol transporters, are they as efficient in reversing intestinal cholesterol transport as plant sterols? Are ABC transporters involved in the reverse transport of other lipid soluble compounds such as lipid soluble drugs? Will the physiological and therapeutic manipulation of ABC transporters modify intestinal FA, cholesterol, sterol, and lipophilic drug absorption in animals and humans? These questions remain to be answered.
To date, the most convincing data supporting the existence of a transporter for cholesterol absorption is provided by studies of the hypocholesterolemic drug, ezetimibe (Zetia®, Schering-Plough) (158,159). After being metabolized in the liver, ezetimibe returns to the intestinal lumen to potently inhibit cholesterol absorption. Although the mechanism by which ezetimibe inhibits intestinal cholesterol absorption is far from clear, inhibition of Niemann-Pick C1-like protein (160), a lipid transporter which has been recently demonstrated to be a binding target for ezetimibe (161), has been suggested. Other possible mechanisms of action include disruption of sterol uptake by the brush border membrane (162) and inhibition of the endocytosis of cholesterol-rich microdomains secondary to binding of ezetimibe to the aminopeptidase, N(CD13) (163). A better understanding of how this drug inhibits cholesterol absorption could potentially provide new and useful information regarding the mechanism of absorption of lipophilic drugs and xenobiotics.
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