A Newly Integrated Model for Intestinal Cholesterol Absorption and Efflux Reappraises How Plant Sterol Intake Reduces Circulating Cholesterol Levels
A Newly Integrated Model for Intestinal Cholesterol Absorption and Efflux Reappraises How Plant Sterol Intake Reduces Circulating Cholesterol Levels
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DOI：
10.3390/nu11020310
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发表时间：
2019-02
期刊：
影响因子：
5.9
通讯作者：
Takanari Nakano;I. Inoue;T. Murakoshi
中科院分区：
文献类型：
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作者：
Takanari Nakano;I. Inoue;T. Murakoshi
胆固醇的动态平衡是通过新陈代谢、肠道吸收和肠道排泄的平衡来维持的。小肠通过吸收和排泄胆固醇来促进胆固醇的稳态，后者被称为跨肠道胆固醇外流(Tice)。由于内源性胆固醇的排泄效率与动脉粥样硬化的发展呈负相关，TICE提供了一个有吸引力的治疗靶点。因此，有必要阐明这一机制。我们已经证明，在小鼠的肠道灌流实验中，肠道胆固醇吸收和TICE呈负相关。在这篇综述中，我们总结了从13篇现有文献中获得的28对吸收效率和粪便中性甾醇排泄量的数据集，这些数据集是Tice的替代标记物，表明这种负相关关系几乎与假设一致。然后，我们提供了一个双向流量模型，该模型考虑了同一段中发生的吸收和Tice。在这个模型中，肠上皮细胞的刷状缘膜(BBM)作为胆固醇通量的分界线，使相反的通量具有竞争性，并被共享的BBM定位的转运体、ATP结合盒G5/G8和Niemann-Pick C1-like 1协调。此外，该想法被应用于研究过量的植物甾醇/斯坦醇(PS)摄入如何降低循环胆固醇水平，因为机制尚不清楚。我们认为，不可吸收的PS反复穿梭于BBM和管腔之间，并促进伴随的胆固醇外流。此外，PSS在化学上类似于胆固醇，可能会干扰将胆固醇运输到细胞内部的运输机器。
Cholesterol homeostasis is maintained through a balance of de novo synthesis, intestinal absorption, and excretion from the gut. The small intestine contributes to cholesterol homeostasis by absorbing and excreting it, the latter of which is referred to as trans-intestinal cholesterol efflux (TICE). Because the excretion efficiency of endogenous cholesterol is inversely associated with the development of atherosclerosis, TICE provides an attractive therapeutic target. Thus, elucidation of the mechanism is warranted. We have shown that intestinal cholesterol absorption and TICE are inversely correlated in intestinal perfusion experiments in mice. In this review, we summarized 28 paired data sets for absorption efficiency and fecal neutral sterol excretion, a surrogate marker of TICE, obtained from 13 available publications in a figure, demonstrating the inverse correlation were nearly consistent with the assumption. We then offer a bidirectional flux model that accommodates absorption and TICE occurring in the same segment. In this model, the brush border membrane (BBM) of intestinal epithelial cells stands as the dividing ridge for cholesterol fluxes, making the opposite fluxes competitive and being coordinated by shared BBM-localized transporters, ATP-binding cassette G5/G8 and Niemann-Pick C1-like 1. Furthermore, the idea is applied to address how excess plant sterol/stanol (PS) intake reduces circulating cholesterol level, because the mechanism is still unclear. We propose that unabsorbable PS repeatedly shuttles between the BBM and lumen and promotes concomitant cholesterol efflux. Additionally, PSs, which are chemically analogous to cholesterol, may disturb the trafficking machineries that transport cholesterol to the cell interior.