IIAEK Targets Intestinal Alkaline Phosphatase (IAP) to Improve Cholesterol Metabolism with a Specific Activation of IAP and Downregulation of ABCA1.
IIAEK Targets Intestinal Alkaline Phosphatase (IAP) to Improve Cholesterol Metabolism with a Specific Activation of IAP and Downregulation of ABCA1.
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DOI：
10.3390/nu12092859
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发表时间：
2020-09-18
期刊：
影响因子：
5.9
通讯作者：
Nagaoka S
中科院分区：
文献类型：
--
作者：
Takeuchi A;Hisamatsu K;Okumura N;Sugimitsu Y;Yanase E;Ueno Y;Nagaoka S
IIAEK（Ile-Ile-Ala-Glu-Lys，lactostatin）是从牛乳β-乳球蛋白中提取的一种新型降胆固醇五肽。然而，IIAEK介导的抑制肠道胆固醇吸收的分子机制尚不清楚。因此，我们评估了IIAEK对肠道胆固醇代谢的影响，在人类肠道模型中使用Caco-2细胞。我们发现，IIAEK显着降低肠道胆固醇代谢相关基因的表达，特别是ATP结合盒转运蛋白A1（ABCA 1）。随后，我们化学合成了一种新的分子探针，IIXEK，它可以可视化的复合物的目标蛋白与光亲和标记IIAEK的荧光物质。通过对大鼠小肠粘膜和Caco-2细胞的肠脂筏组分的IIXEK光亲和标记和MS分析，我们鉴定了肠碱性磷酸酶（IAP）作为与IIAEK相互作用的特异性分子，并发现了与IIAEK结合的共同氨基酸序列GFYLFVEGGR。IIAEK可显著增加Caco-2细胞IAP mRNA和蛋白水平，降低ABCA 1 mRNA和蛋白水平。总之，我们发现IIAEK靶向IAP，通过一种新的信号通路，涉及IAP的特异性激活和肠道ABCA 1的下调，以改善胆固醇代谢。
IIAEK (Ile-Ile-Ala-Glu-Lys, lactostatin) is a novel cholesterol-lowering pentapeptide derived from bovine milk β-lactoglobulin. However, the molecular mechanisms underlying the IIAEK-mediated suppression of intestinal cholesterol absorption are unknown. Therefore, we evaluated the effects of IIAEK on intestinal cholesterol metabolism in a human intestinal model using Caco-2 cells. We found that IIAEK significantly reduced the expression of intestinal cholesterol metabolism-associated genes, particularly that of the ATP-binding cassette transporter A1 (ABCA1). Subsequently, we chemically synthesized a novel molecular probe, IIXEK, which can visualize a complex of target proteins interacting with photoaffinity-labeled IIAEK by fluorescent substances. Through photoaffinity labeling and MS analysis with IIXEK for the rat small intestinal mucosa and intestinal lipid raft fractions of Caco-2 cells, we identified intestinal alkaline phosphatase (IAP) as a specific molecule interacting with IIAEK and discovered the common IIAEK-binding amino acid sequence, GFYLFVEGGR. IIAEK significantly increased IAP mRNA and protein levels while decreasing ABCA1 mRNA and protein levels in Caco-2 cells. In conclusion, we found that IIAEK targets IAP to improve cholesterol metabolism via a novel signaling pathway involving the specific activation of IAP and downregulation of intestinal ABCA1.
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