CLCC1 promotes hepatic neutral lipid flux and nuclear pore complex assembly

Mathiowetz, A. J.; Meymand, E. S.; Deol, K. K.; Parlakgul, G.; Lange, M.; Pang, S. P.; Roberts, M. A.; Torres, E. F.; Jorgens, D. M.; Zalpuri, R.; Kang, M.; Boone, C.; Zhang, Y.; Morgens, D. W.; Tso, E.; Zhou, Y.; Talukdar, S.; Levine, T.; Ku, G.; Arruda, A. P.; Olzmann, J.

doi:10.1101/2024.06.07.597858

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bioRxiv · 10.1101/2024.06.07.597858

CLCC1 promotes hepatic neutral lipid flux and nuclear pore complex assembly

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Abstract

Imbalances in lipid storage and secretion lead to the accumulation of hepatocyte lipid droplets (LDs) (i.e., hepatic steatosis). Our understanding of the mechanisms that govern the channeling of hepatocyte neutral lipids towards cytosolic LDs or secreted lipoproteins remains incomplete. Here, we performed a series of CRISPR-Cas9 screens under different metabolic states to uncover mechanisms of hepatic neutral lipid flux. Clustering of chemical-genetic interactions identified CLIC-like chloride channel 1 (CLCC1) as a critical regulator of neutral lipid storage and secretion. Loss of CLCC1 resulted in the buildup of large LDs in hepatoma cells and knockout in mice caused liver steatosis. Remarkably, the LDs are in the lumen of the ER and exhibit properties of lipoproteins, indicating a profound shift in neutral lipid flux. Finally, remote homology searches identified a domain in CLCC1 that is homologous to yeast Brl1p and Brr6p, factors that promote the fusion of the inner and outer nuclear envelopes during nuclear pore complex assembly. Loss of CLCC1 lead to extensive nuclear membrane herniations, consistent with impaired nuclear pore complex assembly. Thus, we identify CLCC1 as the human Brl1p/Brr6p homolog and propose that CLCC1-mediated membrane remodeling promotes hepatic neutral lipid flux and nuclear pore complex assembly.

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Mathiowetz, A. J., Meymand, E. S., Deol, K. K., Parlakgul, G., Lange, M., Pang, S. P., Roberts, M. A., Torres, E. F., Jorgens, D. M., Zalpuri, R., Kang, M., Boone, C., Zhang, Y., Morgens, D. W., Tso, E., Zhou, Y., Talukdar, S., Levine, T., Ku, G., Arruda, A. P., Olzmann, J.. 2024-06-08. CLCC1 promotes hepatic neutral lipid flux and nuclear pore complex assembly. https://doi.org/10.1101/2024.06.07.597858

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