CLCC1 governs ER bilayer equilibration to maintain lipid homeostasis.

Orchestration of lipid production, storage and mobilization is vital for cellular and systemic homeostasis(1,2). Dysfunctional plasma lipid control represents the major risk factor for cardiometabolic diseases-the leading cause of human mortality(3,4). 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 gut(5,6). 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 process(7-10). 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 TMEM41B(11,12) 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 infection(13-16), we anticipate that future work will elucidate a homeostatic control mechanism intrinsic to ER function in lipid biogenesis and distribution.