College of Life Sciences, Taikang Center for Life and Medical Sciences, Taikang Medical School, Hubei Key Laboratory of Cell Homeostasis, Wuhan University, Wuhan, China.
Heart Center, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830054, Xinjiang, China.
Nat Commun. 2023 Oct 13;14(1):6469. doi: 10.1038/s41467-023-42179-5.
Niemann-Pick C1-like 1 (NPC1L1) is essential for intestinal cholesterol absorption. Together with the cholesterol-rich and Flotillin-positive membrane microdomain, NPC1L1 is internalized via clathrin-mediated endocytosis and transported to endocytic recycling compartment (ERC). When ERC cholesterol level decreases, NPC1L1 interacts with LIMA1 and moves back to plasma membrane. However, how cholesterol leaves ERC is unknown. Here, we find that, in male mice, intracellular bile acids facilitate cholesterol transport to other organelles, such as endoplasmic reticulum, in a non-micellar fashion. When cholesterol level in ERC is decreased by bile acids, the NPC1L1 carboxyl terminus that previously interacts with the cholesterol-rich membranes via the ALAL residues dissociates from membrane, exposing the QKR motif for LIMA1 recruitment. Then NPC1L1 moves back to plasma membrane. This study demonstrates an intracellular cholesterol transport function of bile acids and explains how the substantial amount of cholesterol in NPC1L1-positive compartments is unloaded in enterocytes during cholesterol absorption.
尼曼-匹克 C1 样蛋白 1（NPC1L1）对于肠道胆固醇吸收至关重要。NPC1L1 与富含胆固醇和 Flotillin 的膜微区一起，通过网格蛋白介导的内吞作用内化，并被转运到内吞循环隔间（ERC）。当 ERC 中的胆固醇水平降低时，NPC1L1 与 LIMA1 相互作用并返回质膜。然而，胆固醇离开 ERC 的方式尚不清楚。在这里，我们发现，在雄性小鼠中，细胞内胆汁酸以非胶束的方式促进胆固醇向内质网等其他细胞器的转运。当 ERC 中的胆固醇水平因胆汁酸而降低时，先前通过 ALAL 残基与富含胆固醇的膜相互作用的 NPC1L1 羧基末端与膜解离，暴露出用于 LIMA1 募集的 QKR 基序。然后 NPC1L1 回到质膜。这项研究证明了胆汁酸的细胞内胆固醇转运功能，并解释了在胆固醇吸收过程中，NPC1L1 阳性隔室中大量的胆固醇是如何从肠细胞中卸载的。
