Science：肠道如何吸收胆固醇？新的关键因子被锁定
- ①小鼠中，小肠肠细胞表达的转运蛋白Aster调节对膳食胆固醇的吸收；
- ②小鼠口服胆固醇后，Aster-B蛋白富集到小肠肠细胞刷状缘，Aster-B/C双敲除阻碍胆固醇吸收，并抵抗食源性高胆固醇血症；
- ③机制上，Aster位于NPC1L1下游，NPC1L1使膳食胆固醇在刷状缘沉积，以招募Aster到肠细胞顶端质膜，Aster将胆固醇转移到内质网，其缺失导致质膜上胆固醇积累、内质网胆固醇耗竭；
- ④用小分子抑制剂AI-3d靶向Aster通路，可减少小鼠对膳食胆固醇的吸收。
主编推荐语
高胆固醇血症增加心血管疾病风险。小肠对膳食胆固醇的吸收是影响全身胆固醇稳态的一个重要因素。这一吸收过程始于NPC1L1将游离胆固醇沉积在肠细胞质膜上，而后胆固醇移动到内质网，在那里被酯化进而包装成乳糜微粒。然而，胆固醇如何从质膜移动到内质网，其机制尚不清楚。Science最新发表的一项研究填补了这一空白，发现Aster蛋白作用于NPC1L1下游，在胆固醇从小肠肠细胞质膜向内质网移动的过程中发挥关键作用。这些发现为减少肠道的胆固醇吸收从而改善高胆固醇症，提供了新的药物靶点。
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Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake
Aster依赖性的非囊泡运输促进膳食胆固醇摄取
10.1126/science.adf0966
11-09, Article
Abstract & Authors:展开
Abstract:收起
Intestinal absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1) assists in the initial step of dietary cholesterol uptake, but how cholesterol moves downstream of NPC1L1 is unknown. We show that Aster-B and Aster-C are critical for nonvesicular cholesterol movement in enterocytes. Loss of NPC1L1 diminishes accessible plasma membrane (PM) cholesterol and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate PM cholesterol and show endoplasmic reticulum cholesterol depletion. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, the Aster pathway can be targeted with a small-molecule inhibitor to manipulate cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption.
First Authors:
Alessandra Ferrari,Emily Whang
Correspondence Authors:
Peter Tontonoz
All Authors:
Alessandra Ferrari,Emily Whang,Xu Xiao,John P Kennelly,Beatriz Romartinez-Alonso,Julia J Mack,Thomas Weston,Kai Chen,Youngjae Kim,Marcus J Tol,Lara Bideyan,Alexander Nguyen,Yajing Gao,Liujuan Cui,Alexander H Bedard,Jaspreet Sandhu,Stephen D Lee,Louise Fairall,Kevin J Williams,Wenxin Song,Priscilla Munguia,Robert A Russell,Martin G Martin,Michael E Jung,Haibo Jiang,John W R Schwabe,Stephen G Young,Peter Tontonoz
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