2026年2月25日出版的《自然》杂志发表了中国科学家的一项最新研究成果。来自北京大学的陈晓伟等人的研究发现CLCC1调控内质网双分子层平衡以维持脂质稳态。

本研究表明内质网蛋白CLCC1通过参与磷脂的跨双分子层平衡来调节细胞脂质分配，从而调节全身脂质稳态。CLCC1与磷脂重组酶TMEM41B合作，识别不平衡的双分子层，促进脂质重组，从而支持脂蛋白的生物生成和随后的大量脂质转运。CLCC1或TMEM41B的缺失导致巨大的管腔脂滴出现，被不平衡的内质网双层包围，从而加速代谢功能障碍相关的肝脂肪性肝炎的发病。结果表明，磷脂在内质网处的混乱是建立动态平衡所必需的。考虑到从分解代谢自噬到病毒感染等许多生物过程都需要跨双分子层磷脂平衡，小组预计未来的工作将阐明内质网功能在脂质生物发生和分布中的内在稳态控制机制。

据介绍，脂质生产、储存和动员的协调对细胞和系统的稳态至关重要。血脂控制不正常是导致心脏代谢疾病的主要危险因素，而心脏代谢疾病是导致人类死亡的主要原因。在细胞景观中，内质网（ER）是脂质合成和分泌的中心枢纽，特别是在肝脏代谢活跃的肝细胞或肠道细胞中。脂质转运脂蛋白最初组装在内质网管腔中，需要中性脂和磷脂跨膜转移到管腔载脂蛋白B （APOB）上，这一过程定义不明确。

附：英文原文

Title: CLCC1 governs ER bilayer equilibration to maintain lipid homeostasis

Author: Wu, Lingzhi, Wang, Jianqin, Wang, Yawei, Yang, Junhan, Yao, Yuanhang, Wang, Yonglun, Huang, Dong, Hu, Yating, Xu, Xinxuan, Wang, Renqian, Du, Wenjing, Shi, Yiting, Li, Quan, Liu, Lu, Zhu, Yuangang, Li, Shijie, Chen, Feng-Jung, Zhang, Xiuqin, Wang, Xiao, Guo, Qiang, Xu, Li, Li, Peng, Chen, Xiao-Wei

Issue&Volume: 2026-02-25

Abstract: Orchestration of lipid production, storage and mobilization is vital for cellular and systemic homeostasis1,2. Dysfunctional plasma lipid control represents the major risk factor for cardiometabolic diseases—the leading cause of human mortality3,4. Within the cellular landscape, the endoplasmic reticulum (ER) is the central hub of lipid synthesis and secretion, particularly in metabolically active hepatocytes in the liver or enterocytes in the gut5,6. Initially assembled in the ER lumen, lipid-ferrying lipoproteins necessitate the cross-membrane transfer of both neutral and phospholipids onto the lumenal apolipoprotein B (APOB), in a poorly defined process7,8,9,10. Here we show that the ER protein CLCC1 regulates cellular lipid partition and, consequently, systemic lipid homeostasis by participating in trans-bilayer equilibration of phospholipids. CLCC1 partners with the phospholipid scramblase TMEM41B11,12 to recognize imbalanced bilayers and promote lipid scrambling, thereby supporting lipoprotein biogenesis and the subsequent bulk lipid transport. Loss of CLCC1 or TMEM41B leads to the emergence of giant lumenal lipid droplets enclosed by imbalanced ER bilayers and, consequently, accelerated pathogenesis of metabolic-dysfunction-associated liver steatohepatitis. The results reveal that phospholipid scrambling at the ER is essential for establishing a dynamic equilibrium. Considering the requirement of trans-bilayer phospholipid equilibration in numerous biological processes, ranging from catabolic autophagy to viral infection13,14,15,16, we anticipate that future work will elucidate a homeostatic control mechanism intrinsic to ER function in lipid biogenesis and distribution.

DOI: 10.1038/s41586-026-10161-y

Source: https://www.nature.com/articles/s41586-026-10161-y