CLCC1 governs ER bilayer equilibration to maintain lipid homeostasis

Nature

by Lingzhi Wu

February 26, 2026

AI-Generated Deep Dive Summary

A recent study reveals that the protein CLCC1 plays a critical role in maintaining lipid homeostasis by regulating phospholipid scrambling at the endoplasmic reticulum (ER). This process ensures the proper distribution of lipids, which is essential for cellular and systemic health. When CLCC1 or its partner TMEM41B are absent, cells accumulate giant lipid droplets within the ER lumen, leading to severe metabolic dysfunction and liver disease. The research highlights how lipid scrambling— the movement of phospholipids between bilayer leaflets—supports lipoprotein production and overall lipid transport. The study utilized advanced imaging techniques like cryo-electron tomography and correlative light and electron microscopy (CLEM) to visualize these lipid storage abnormalities. In TMEM41B-deficient cells, researchers observed massive lipid droplets surrounded by curved ER membranes, indicating a failure in normal lipid partitioning. This finding underscores the importance of phospholipid scrambling in maintaining dynamic equilibrium within the ER. Without this process, cells struggle to manage lipid imbalances, resulting in pathologies such as liver steatohepatitis. The discovery has broader implications for understanding lipid-related metabolic diseases and other processes that rely on trans-bilayer lipid movement. For example, lipid scrambling is also involved in autophagy and viral infection mechanisms. Future research could explore how this equilibrium is regulated and its role in various biological systems

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Originally published on Nature on 2/26/2026