J Lipid Res：宋保亮等揭示降胆固醇药物“益适纯”抑制小肠胆固醇吸收的机制

“益适纯”（Ezetimibe，依泽替米贝）是临床应用的胆固醇吸收抑制剂，它在小肠中是如何发挥作用的并不清楚。

7月17日，《脂质研究杂志》（《The Journal of Lipid Research》）在线发表了上海生科院生化与细胞所宋保亮研究组和李伯良研究组的合作研究论文“Ezetimibe blocks the internalization of NPC1L1 and cholesterol in mouse small intestine”。该研究成果揭示了“益适纯”在小肠内抑制饮食胆固醇吸收的机制。

谢畅博士和博士研究生周章森等首次观察到小鼠小肠中NPC1L1蛋白通过囊泡内吞转运饮食胆固醇进入肠上皮细胞。NPC1L1特异性表达在小肠绒毛吸收细胞，另一种胆固醇转运关键蛋白ACAT2主要存在于肠上皮细胞靠近刷状缘面的胞质中，负责将NPC1L1吸收的胆固醇合成胆固醇酯进而包装到乳糜微粒中，这两种蛋白都在小肠的空肠和回肠区段有高表达。当肠道中缺失胆固醇时，NPC1L1集中在肠上皮细胞刷状缘面。食物中的胆固醇诱导携带有胆固醇的NPC1L1从刷状缘面以囊泡内吞形式向胞内转运。而“益适纯”就是通过阻断NPC1L1的内吞从而抑制胆固醇吸收。这项研究工作深入揭示了饮食胆固醇吸收的机制，并阐明了降胆固醇药物“益适纯”在体内的作用原理。

该课题获得了国家科技部、国家自然科学基金委和上海市科委的经费支持。

doi:10.1194/jlr.M027359
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Ezetimibe blocks the internalization of NPC1L1 and cholesterol in mouse small intestine

Chang Xie, Zhang-Sen Zhou, Na Li, Yan Bian, Yong-Jian Wang, Li-Juan Wang, Bo-Liang Li and Bao-Liang Song*

The multiple transmembrane protein NPC1L1 is essential for intestinal cholesterol absorption. ACAT2 is another important protein for cholesterol absorption by providing cholesteryl esters to chylomicrons. Ezetimibe binds to NPC1L1 and is a clinically used cholesterol absorption inhibitor. Recent studies in cultured cells have shown that NPC1L1 mediates cholesterol uptake through vesicular endocytosis that can be blocked by ezetimibe. However, how NPC1L1 and ezetimibe work in small intestine is unknown. In this study, we found that NPC1L1 distributed in enterocytes of villi and transit-amplifying cells of crypts. ACAT2 was mainly presented in the apical cytoplasm of enterocytes, whereas ACAT1 was localized in Paneth cells of crypts and mesenchymal cells of villi. Both NPC1L1 and ACAT2 were highly expressed in jejunum and ileum. In the absence of cholesterol, NPC1L1 was localized on the brush border of enterocytes. Dietary cholesterol induced the internalization of NPC1L1 to the sub-apical sites beneath the brush border and became partially colocalized with endosome marker Rab11. Notably, ezetimibe blocked the internalization of NPC1L1 and cholesterol and caused their retention in the plasma membrane. In summary, this study demonstrates that NPC1L1 mediates cholesterol entering enterocytes through vesicular endocytosis, and ezetimibe blocks this step in vivo.