Researchers discover a molecular mechanism involved in the transport of cholesterol cells


Confocal microscopy image showing the SNX13 protein (green) in regions of the endoplasmic reticulum in contact with lipid droplets (blue) and lysosomes in which the BMP lipid is present (red).


From left to right, professors of the Faculty of Medicine and Health Sciences Carles Enrich and Albert Lu, first author of the article.

From left to right, professors of the Faculty of Medicine and Health Sciences Carles Enrich and Albert Lu, first author of the article.

A team from UB and the August Pi i Sunyer Institute for Biomedical Research (IDIBAPS) has identified a mechanism involved in the movement of cholesterol inside cells. The study, published in the Journal of Cell Biology, shows how the SNX13 protein plays a key role in transporting this lipid out of liposomes, the organelles that ensure cellular digestion. These results could have implications for the future development of treatments for pathologies caused by dysfunctions in the intracellular transport of cholesterol, such as Niemann-Pick disease type C1.

The study counts on the participation of professors from the Faculty of Medicine and Health Sciences at UB and the Center for Biomedical Research CELLEX (IDIBAPS-UB) Albert Lu, first author of the article, and Carles Enrich, as well as researchers from Stanford University.

The Harmful Effects of Unbalanced Cholesterol Levels

Most of the cholesterol used by the cells comes from outside, reaching the lysosomes where it is distributed in different intracellular compartments. However, there remain unresolved questions related to the precise molecular events that regulate the outflow of cholesterol from this organelle and its transport to the membrane and the cellular endoplasmic reticulum. The objective of this study was to investigate the mechanism by which cholesterol exists in lysosomes. “This process requires the coordinated action of transporters NPC1 and NPC2 which, together with the lysosomal lipid bis(monoaclyglycero)phosphate (BMP), mobilize and export free cholesterol”, notes Carles Enrich.

The regulation of intracellular cholesterol trafficking and the amount received by cellular organelles is important for the balance—or homeostasis—of cholesterol in the cell. Errors or malfunctions in its transport cause an imbalance that causes disorders such as Niemann-Pick type C disease. This pathology, incurable to date, is produced by mutations in the lysosomal cholesterol transporters NPC1 and NPC2. This disease prevents the normal metabolism of cholesterol and other fats and has serious effects on the liver, spleen and brain.

Genome-wide CRISPR/Cas9-like genetic testing

In order to identify regulators of cholesterol balance, the researchers performed CRISPR/Cas9-like genetic screens in the genome. This methodology allows a massive and parallel interrogation of the human genome concerning a specific biological process, generating a large amount of data. In this study, screening was applied under normal conditions, but also by blocking the NPC1 protein in order to identify cellular elements capable of exporting cholesterol alongside this transporter.

This strategy has made it possible to identify genes which, when removed, modify intracellular cholesterol or BMP levels. “Our genetic screens have identified a large number of genes involved in the metabolic regulation of cholesterol and BMPs, whose role was unknown to date. In addition, we confirmed a close correlation and regulation between the levels of these lipids”, notes Albert Lu.

One of the molecules involved in this process is SNX13, an endoplasmic reticulum protein that negatively regulates the outflow of cholesterol from lysosomes to the plasma membrane, thereby reducing the amount of this lypid. “Given the absence of NPC1 function, the reduction of SNX13 caused a redistribution of lysosomal cholesterol to the plasma membrane, indicating that SNX13 may be an important regulator in this cholesterol transport pathway,” explains Albert Lu. .

An unexpected vision of regulatory mechanisms

These results offer an unexpected insight into the regulation of these lipids, as there are a few alternative mechanisms – and most of them are unknown – that allow cholesterol to exit when the NPC1 transporter is inhibited or mutated. “We have described an alternative pathway regulated by anexin-A6, and with this new study, we provide new evidence showing that there may be alternative exit pathways for lysosomal cholesterol alongside NPC1,” emphasizes Carles Enrich.

The discovery of molecules capable of reversing the effects caused by the dysfunction of NPC1, such as SNX13, could imply the existence of “future therapeutic targets in the treatment of Niemann-Pick type C disease, since a better knowledge of molecules that participate in the contact between organelles can make it possible to manipulate the transport of lipids and ions and to restore cellular homeostasis”, conclude the researchers.

Reference article:

Lu, A.; Hsieh, F.; Sharma, BR; Vaughn, SR; Enrich, C.; i Pfeffer SR “CRISPR screens for lipid regulators reveal a role for ER-bound SNX13 in lysosomal cholesterol export“. Journal of Cell Biology, December 2021. Doi: https://doi.org/10.1083/jcb.202105060

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