CLCC1 promotes hepatic neutral lipid flux and nuclear pore complex assembly

Nature

by Alyssa J. Mathiowetz

February 26, 2026

AI-Generated Deep Dive Summary

A study published in *Nature Cell Biology* reveals that CLCC1, a protein previously uncharacterized in lipid metabolism, plays a critical role in regulating neutral lipid storage and secretion in hepatocytes. Using advanced CRISPR–Cas9 screens under various metabolic conditions, researchers identified CLCC1 as a key factor influencing whether neutral lipids are stored as cytosolic lipid droplets or secreted as very low-density lipoproteins (VLDLs). Loss of CLCC1 disrupts this balance, leading to the accumulation of large lipid droplets in hepatoma cells and liver steatosis in mice. This finding highlights a novel mechanism by which neutral lipid flux is regulated, with implications for understanding and treating hepatic steatosis. The study also uncovered an unexpected connection between CLCC1 and nuclear pore complex assembly. When CLCC1 was knocked out, researchers observed nuclear membrane herniations and reduced nuclear pores in hepatocytes. Homology searches revealed that CLCC1 shares a domain with yeast proteins Brl1 and Brr6, which are known to promote nuclear envelope fusion during nuclear pore formation. Molecular dynamics simulations and mutagenesis studies suggest that CLCC1 mediates membrane bending and fusion, processes essential for both lipid droplet biogenesis and nuclear pore assembly. This dual role underscores the importance of membrane dynamics in regulating cellular organelle formation. The research provides new insights into the interplay between lipid metabolism and nuclear organization. By identifying CLCC1 as a critical regulator of neutral lipid flux and nuclear pore complex assembly, the study opens up potential therapeutic avenues for targeting hepatic steatosis and related metabolic disorders. The findings also highlight the importance of understanding how cellular membranes are dynamically remodeled to maintain proper organelle function and overall cell health. This work contributes to our growing knowledge of lipid metabolism and its role in liver disease, offering a foundation for future studies aimed at developing targeted therapies.

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Originally published on Nature on 2/26/2026