A team of scientists at the University of California, Berkeley, has identified a protein that regulates how liver cells store and secrete fat, processes central to the development of fatty liver disease. The findings, published today in Nature, reveal that the CLCC1 protein is a membrane-remodeling factor with essential roles in liver physiology and lipid metabolism. They also find that the same protein enables the proper assembly of nuclear pores, the gateways that control molecular traffic into and out of the cell nucleus.
An electron microscopy image shows lipid droplets (gray) accumulating around an altered nuclear membrane (purple) in liver cells lacking CLCC1.
The study was led by James Olzmann and Ana Paula Arruda, professors in UC Berkeley’s Departments of Metabolic Biology & Nutrition (MBN) and Molecular & Cell Biology (MCB), and spearheaded by former graduate student Alyssa Mathiowetz, PhD ’24 Metabolic Biology, and current MCB graduate student Emily Meymand.
Mathiowetz and Meymand, the paper’s co-first authors, began the project by conducting a coordinated series of genome-wide and targeted, CRISPR-based genetic screens. This systematic, discovery-based strategy was designed to identify genes that govern fat partitioning between storage in lipid droplets and secretion as lipoproteins. This decision—whether fat is stored or exported—is a fundamental determinant of liver health, and its dysregulation underlies fatty liver disease and associated metabolic disorders. Parallel screens across 11 metabolic conditions identified CLCC1 as a previously unrecognized and high-confidence regulator of hepatic lipid metabolism. Disrupting CLCC1 in human hepatocyte cell lines caused dramatic fat accumulation and impaired lipoprotein secretion.
To test the physiological relevance of these findings, the team deleted the CLCC1-producing gene in mouse hepatocytes. The result was striking: without CLCC1, mice developed severe fatty liver disease and a near-complete loss of circulating lipoproteins, demonstrating that the protein is essential for maintaining lipid balance in the liver.
Further analyses revealed that CLCC1 is a core regulator of lipid storage and secretion in liver cells, and its loss leads to a profound disruption of intracellular lipid flux. Hepatocytes lacking CLCC1 accumulated abnormally large, lipoprotein-like structures trapped within the endoplasmic reticulum, instead of forming conventional cytoplasmic lipid droplets.
A microscopy image shows the difference in accumulation in lipid droplets (blue) between liver cells that contain (left) and lack (right) the CLCC1 protein.
To better understand how CLCC1 functions at cellular membranes, the team turned to protein structure predictions. Structural modeling performed by University College London professor Tim Levine revealed unexpected homology between CLCC1 and yeast proteins that promote membrane fusion during nuclear pore complex assembly. Guided by this insight, the UC Berkeley research team examined the nuclear architecture of cells lacking CLCC1. They found that the protein is required for nuclear pore insertion, with cells deficient in CLCC1 exhibiting nuclear membrane herniations and reduced nuclear pores—hallmarks of defective nuclear pore assembly. Despite decades of study, the protein machinery responsible for inserting nuclear pores into the nuclear envelope in mammalian cells had remained unknown.
“When taken together, these findings identify CLCC1 as the long-sought protein that enables membranes to fuse during nuclear pore assembly, while also establishing an independent role in hepatic lipid storage and secretion,” Olzmann explained.
While the two functions of CLCC1 occur in distinct cellular contexts, both rely on a shared membrane-remodeling activity. Structural modeling, molecular dynamics simulations, and targeted mutational analyses suggest a compelling model in which CLCC1 assembles into oligomeric complexes that bend and fuse lipid bilayers, providing a mechanistic basis for its roles in lipid metabolism and nuclear pore assembly.
“Our study highlights how systematic genetic discovery, combined with structural insight, can uncover unexpected biology and reveal fundamental cellular mechanisms relevant to the study of human disease,” Arruda added.
Additional co-authors include MBN professor Güneş Parlakgül; Arruda lab postdoctoral researcher Leonardo L. Artico; current and former Olzmann lab members Emily Torres, Kirandeep K. Deol, Mike Lange, Stephany Pang, Cody Doubravsky, and Melissa Roberts; Electron Microscope Laboratory staff members Danielle Jorgens, Reena Zalpuri, and Misun Kang; Metabolic Biology PhD student Casadora Boone; alum Yaohuan Zhang; and David Morgens, a former postdoctoral researcher in the lab of UC Berkeley Professor Britt Glaunsinger.
Read More
- CLCC1 promotes hepatic neutral lipid flux and nuclear pore complex assembly (Nature)
- Olzmann Lab website
- Arruda Lab website
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