2. Academic Validation
  3. CLCC1 governs ER bilayer equilibration to maintain lipid homeostasis

CLCC1 governs ER bilayer equilibration to maintain lipid homeostasis

  • Nature. 2026 Apr;652(8109):471-480. doi: 10.1038/s41586-026-10161-y.
Lingzhi Wu # 1,  Jianqin Wang # 2,  Yawei Wang # 3,  Junhan Yang 4,  Yuanhang Yao 1,  Yonglun Wang 1,  Dong Huang 1,  Yating Hu 1,  Xinxuan Xu 1,  Renqian Wang 1,  Wenjing Du 4,  Yiting Shi 1,  Quan Li 1,  Lu Liu 1,  Yuangang Zhu 1,  Shijie Li 5,  Feng-Jung Chen 5,  Xiuqin Zhang 1,  Xiao Wang 1,  Qiang Guo 6,  Li Xu 7,  Peng Li 8 9,  Xiao-Wei Chen 10 11 12
Affiliations

Affiliations

  • 1 State Key Laboratory of Membrane Biology and Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China.
  • 2 Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
  • 3 PKU-THU Joint Center for Life Sciences, Peking University, Beijing, China.
  • 4 State Key Laboratory of Membrane Biology, Peking-Tsinghua Joint Center for Life Sciences, Scholar of Life Sciences, Peking University, Beijing, China.
  • 5 Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China.
  • 6 State Key Laboratory of Membrane Biology, Peking-Tsinghua Joint Center for Life Sciences, Scholar of Life Sciences, Peking University, Beijing, China. [email protected].
  • 7 Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China. [email protected].
  • 8 Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China. [email protected].
  • 9 State Key Laboratory of Metabolic Dysregulation & Prevention and Treatment of Esophageal Cancer, Tianjian Laboratory of Advanced Biomedical Sciences, Academy of Medical Sciences, Zhengzhou University, Beijing, China. [email protected].
  • 10 State Key Laboratory of Membrane Biology and Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, China. [email protected].
  • 11 PKU-THU Joint Center for Life Sciences, Peking University, Beijing, China. [email protected].
  • 12 Institute of Advanced Clinical Medicine, Peking University, Beijing, China. [email protected].
  • # Contributed equally.
PMID: 41741642 DOI: 10.1038/s41586-026-10161-y
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 process7-10. 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 Infection13-16, we anticipate that future work will elucidate a homeostatic control mechanism intrinsic to ER function in lipid biogenesis and distribution.

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