Transintestinal cholesterol excretion (TICE) is a major route for eliminating cholesterol from the body and a potential therapeutic target for hypercholesterolemia. The underlying mechanism, however, is largely unclear, and its contribution to cholesterol disposal from the body is obscured by the counteracting process of intestinal cholesterol reabsorption. To determine the quantity of TICE independent from its reabsorption, we studied two models of decreased intestinal cholesterol absorption. Cholesterol absorption was inhibited either by ezetimibe or, indirectly, by the genetic inactivation of the intestinal apical sodium-dependent bile acid transporter (ASBT; SLC10A2). Both ezetimibe treatment and Asbt inactivation virtually abrogated fractional cholesterol absorption (from 46% to 4% and 6%, respectively). In both models, fecal neutral sterol excretion and net intestinal cholesterol balance were considerably higher than in control mice (5- and 7-fold, respectively), suggesting that, under physiological conditions, TICE is largely reabsorbed. In addition, the net intestinal cholesterol balance was increased to a similar extent but was not further increased when the models were combined, suggesting that the effect on cholesterol reabsorption was already maximal under either condition alone. On the basis of these findings, we hypothesize that the inhibition of cholesterol (re)absorption combined with stimulating TICE will be most effective in increasing cholesterol disposal.

中文翻译：

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经肠排泄的胆固醇的有效重吸收是小鼠胆固醇处理的重要决定因素。


肠胆固醇排泄（TICE）是消除体内胆固醇的主要途径，也是高胆固醇血症的潜在治疗靶点。然而，其根本机制在很大程度上尚不清楚，并且其对体内胆固醇处理的贡献被肠道胆固醇重吸收的抵消过程所掩盖。为了确定与其重吸收无关的 TICE 量，我们研究了两种肠道胆固醇吸收减少的模型。依折麦布或肠道顶端钠依赖性胆汁酸转运蛋白（ASBT； SLC10A2 ）的基因失活间接抑制胆固醇吸收。依折麦布治疗和Asbt灭活实际上消除了胆固醇吸收分数（分别从 46% 降至 4% 和 6%）。在这两个模型中，粪便中性甾醇排泄和净肠道胆固醇平衡显着高于对照小鼠（分别是 5 倍和 7 倍），这表明在生理条件下，TICE 大部分被重吸收。此外，当模型组合时，净肠道胆固醇平衡增加到类似程度，但没有进一步增加，这表明在单独的任何一种情况下，对胆固醇重吸收的影响已经最大。基于这些发现，我们假设抑制胆固醇（再）吸收与刺激 TICE 相结合将最有效地增加胆固醇的处理。