A genetic dissection of intestinal fat-soluble vitamin and carotenoid absorption.
A genetic dissection of intestinal fat-soluble vitamin and carotenoid absorption.
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肠道脂溶性维生素和类胡萝卜素吸收的基因解剖。
DOI：
10.1093/hmg/ddv072
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发表时间：
2015
影响因子：
3.5
通讯作者：
VonLintig,Johannes
中科院分区：
文献类型：
--
作者：
Widjaja-Adhi,MAiranthiK;Lobo,GlennP;Golczak,Marcin;VonLintig,Johannes
类胡萝卜素目前正在研究其降低慢性病风险和对抗维生素A缺乏症的潜力。令人惊讶的是，对补充这些化合物的饮食的反应在不同的人之间有很大的差异。全基因组研究已经将BCO1基因中常见的遗传多态与这种变异联系在一起。BCO1基因编码一种在肠道中表达的酶，将维生素A原类胡萝卜素转化为维生素A醛。然而，目前还不清楚这种酶如何影响叶黄素等其他类胡萝卜素的生物利用度和代谢。我们在这里提供的证据表明，BCO1是控制类胡萝卜素和脂溶维生素吸收的调控网络的关键组成部分。在这个过程中，β-胡萝卜素被BCO1转化为维生素A，通过维甲酸信号诱导肠道同源框转录因子ISX的表达。随后，ISX与BCO1和SCARB1基因上游保守的DNA结合基序结合。SCARB1编码一种膜蛋白，促进脂溶维生素和类胡萝卜素的吸收。与其作为转录抑制因子的作用一致，ISX缺陷小鼠的肠道中SCARB1蛋白水平显著增加。这种增加导致叶黄素、类胡萝卜素和生育酚在组织中的吸收和积累增加。我们的研究表明，脂溶维生素和类胡萝卜素的吸收受BCO1依赖的负反馈调节控制。因此，我们的发现为人类群体中遗传学和脂溶维生素状态之间的有争议的关系提供了一个分子框架。
Carotenoids are currently investigated regarding their potential to lower the risk of chronic disease and to combat vitamin A deficiency. Surprisingly, responses to dietary supplementation with these compounds are quite variable between individuals. Genome-wide studies have associated common genetic polymorphisms in theBCO1gene with this variability. TheBCO1gene encodes an enzyme that is expressed in the intestine and converts provitamin A carotenoids to vitamin A-aldehyde. However, it is not clear how this enzyme can impact the bioavailability and metabolism of other carotenoids such as xanthophyll. We here provide evidence that BCO1 is a key component of a regulatory network that controls the absorption of carotenoids and fat-soluble vitamins. In this process, conversion of β-carotene to vitamin A by BCO1 induces via retinoid signaling the expression of the intestinal homeobox transcription factor ISX. Subsequently, ISX binds to conserved DNA-binding motifs upstream of theBCO1andSCARB1genes. SCARB1 encodes a membrane protein that facilitates absorption of fat-soluble vitamins and carotenoids. In keeping with its role as a transcriptional repressor, SCARB1 protein levels are significantly increased in the intestine of ISX-deficient mice. This increase results in augmented absorption and tissue accumulation of xanthophyll carotenoids and tocopherols. Our study shows that fat-soluble vitamin and carotenoid absorption is controlled by a BCO1-dependent negative feedback regulation. Thus, our findings provide a molecular framework for the controversial relationship between genetics and fat-soluble vitamin status in the human population.