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The recent identification of the aberrant transport proteins ABCG5 and ABCG8 resulting in sitosterolemia suggests that intestinal uptake of cholesterol is an unselective process, and that discrimination between cholesterol and plant sterols takes place at the level of sterol efflux from the enterocyte. Although plant sterols are structurally very similar to cholesterol, differing only in their side chain length, they are absorbed from the intestine to a markedly lower extent. In order to further evaluate the process of discrimination, three different sterols (cholesterol, campesterol, sitosterol) and their corresponding 5 ␣ -stanols (cholestanol, campestanol, sitostanol) were compared concerning their concentration in the proximal small intestine, in serum, and in bile after a single oral dose of deuterated compounds. The data obtained support the hypothesis that i ) the uptake of sterols and stanols is an extremely rapid process, ii ) discrimination probably takes place on the level of reverse transport back into the gut lumen, iii ) plant stanols are taken up, but not absorbed to a measurable extent, and iv ) the process of discrimination probably also exists at the level of biliary excretion. The range of structural alterations that decrease intestinal absorption and increase biliary excretion is: 1 ) campesterol, 2 ) cholestanol-sitosterol, and 3 ) campestanol-sitostanol. Investigators have been intrigued for more than a decade with the concept that there is a protein-mediated transport system responsible for intestinal uptake of cholesterol (1). The recent identification of the molecular defects underlying phytosterolemia (2, 3) and the lines of evidence supporting the existence of a specific transport protein located in the brush border membrane that possibly mediates intestinal sterol absorption (4-6) has shed new light on the cellular transport of cholesterol and plant sterols. Based on the characterization of sterol uptake in brush border membranes, it is currently hypothesized that the process of intestinal sterol uptake is protein mediated and that the pumping of sterols from the intestine into the enterocyte is unselective. In phytosterolemia, a rare autosomal recessive disorder caused by mutations in the tandem ABC genes, either ABCG5 or ABCG8, affected individuals hyperabsorb and retain not only cholesterol but also plant sterols (7-11). Consequently, it is hypothesized that the ABC transporters G5 and G8 are able to discriminate between cholesterol and other sterols. They are pumping the noncholesterol sterols out of the intestinal cell back into the gut lumen and also into bile, and they are differentiating between the side-chain length and probably also between the stereoselective 5 ␣ saturation of the ⌬ 5 double bond to stanols (12, 13).Plant sterols are structurally related to cholesterol and differ in their chemical structure only due to the presence of an additional methyl (campesterol) or ethyl (sitosterol) group at the C-24 position of the side chain. Stanols differ from the corre...

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In the present study, the effect of leptin on intestinal cholesterol absorption was investigated in C57 BL/6 OlaHsd Lep(ob)/Lep(ob) obese (ob/ob) mice and lean C57 BL/6 (wild-type) mice. Animals were treated either with or without recombinant leptin for 2 wk. Cholesterol absorption was measured by the constant isotope feeding method and indirectly by the ratio of campesterol to cholesterol in serum. In ob/ob mice, cholesterol absorption was significantly higher compared to wild-type mice [83.4 +/- 2.3% (SD) vs. 77.6 +/- 1.5%, P < 0.01]. Treatment with leptin significantly reduced cholesterol absorption in both ob/ob and wild-type mice by 8.5 (P < 0.001) and 5.2% (P < 0.05), respectively. Serum concentrations of campesterol and the ratio of campesterol to cholesterol in ob/ob mice were significantly higher compared to wild-type mice (2.2 +/- 0.3 mg/dL vs. 1.2 +/- 0.3 mg/dL, P< 0.001; and 36.8 +/- 2.8 microg/mg vs. 28.0 +/- 3.3 microg/mg, P < 0.001). After treatment of ob/ob mice with leptin, concentrations of campesterol and its ratio to cholesterol were significantly lower (2.2 +/- 0.3 mg/dL vs. 1.0 +/- 0.2 microg/mg, P < 0.001; and 36.8 +/- 2.8 microg/mg vs. 13.2 +/- 2.2 microg/mg, P < 0.001, respectively). In wild-type mice, the ratio of campesterol to cholesterol in serum was also significantly lower after treatment with leptin (28.0 +/- 3.3 microg/mg vs. 22.6 +/- 5.0 microg/mg, P < 0.05). A significant positive correlation (r = 0.701, P < 0.01) between cholesterol absorption and the ratio of campesterol to cholesterol in serum was found. It is concluded that leptin contributes to intestinal cholesterol absorption in ob/ob mice and lean wild-type mice.