Aster-dependent nonvesicular transport facilitates dietary cholesterol uptake

• 成果类型: Article
• 署名作者: Ferrari, Alessandra; Whang, Emily; Xiao, Xu; Kennelly, John P.; Romartinez-Alonso, Beatriz; Mack, Julia J.; Weston, Thomas; Chen, Kai; Kim, Youngjae; Tol, Marcus J.; Bideyan, Lara; Nguyen, Alexander; Gao, Yajing; Cui, Liujuan; Bedard, Alexander H.; Sandhu, Jaspreet; Lee, Stephen D.; Fairall, Louise; Williams, Kevin J.; Song, Wenxin; Munguia, Priscilla; Russell, Robert A.; Martin, Martin G.; Jung, Michael E.; Jiang, Haibo; Schwabe, John W. R.; Young, Stephen G.; Tontonoz, Peter
• 署名单位: University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of Leicester; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of Hong Kong; University of Western Australia; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; Australian Nuclear Science & Technology Organisation
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-12072
• DOI: 10.1126/science.adf0966
• 发表日期: 2023-11-10
• 关键词: absorption inhibitor; stem-cells; in-vitro; ezetimibe; npc1l1; binding; protein; internalization; MODEL; acat2

摘要

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.