Scientists discover a molecular mechanism involved in cholesterol transport

Researchers from the University of Barcelona (UB) and the Hospital Clínic-Idibaps have discovered a molecular mechanism involved in the transport of cholesterol within cells, which could become a therapeutic target against diseases caused by dysfunctions in intracellular cholesterol transport , such as the Niemann-Pick type C.

The research, published in the Journal of Cell Biology, shows how the SNX13 protein plays a key role in transporting this lipid out of the lysosomes, the organelles responsible for cell digestion.

The work has been carried out by professors from the Faculty of Medicine and Health Sciences of the UB and the CELLEX Biomedical Research Center (IDIBAPS-UB), Albert Lu and Carles Enrich, together with researchers from Stanford University.

Researchers have recalled that most of the cholesterol used by cells comes from the outside, and from there it reaches the lysosomes, where it is distributed to different intracellular compartments.

However, the precise molecular events that regulate the release of cholesterol from this organelle and its subsequent transport to the membrane and the endoplasmic reticulum are still unknown, so the researchers set out to study the mechanism by which cholesterol leaves the lysosomes .

“This process requires the coordinated action of the transporters NPC1 and NPC2 which, together with the lysosomal lipid bis(monoacylglycerol) phosphate (BMP), mobilize and export free cholesterol.”, explained Carles Enrich.

The regulation of intracellular traffic of cholesterol and the amount that the different cellular organelles receive is very important for the balance —or homeostasis— of cholesterol in the cell.

Errors or dysfunctions in its transport cause an imbalance that causes disorders such as Niemann-Pick type C disease, a pathology, currently without a cure, caused by mutations in the lysosomal cholesterol transporters NPC1 and NPC2.

This condition prevents cholesterol and other fats from being metabolized normally and has serious effects on the liver, spleen and brain.

To identify regulators of cholesterol balance, the researchers carried out CRISPR/Cas9-type genetic screens throughout the genome, both under normal conditions and by blocking the NPC1 protein in order to identify cellular components that can export cholesterol in parallel to this conveyor.

This strategy led to the discovery of genes that, when removed, alter intracellular levels of cholesterol or BMP.

“Our genetic screens identified a high number of genes involved in the metabolic regulation of cholesterol and BMP, whose role was not known in this context. Furthermore, we confirmed a close correlation and regulation between the levels of these two lipids.”, underlined Albert Lu.

One of the molecules involved in this process is SNX13, an endoplasmic reticulum protein that negatively regulates the release of cholesterol from lysosomes to the plasma membrane, thus reducing the amount of this lipid.

According to the researchers, these results provide an unexpected insight into the regulation of these lipids, since there are few and mostly unknown alternative mechanisms that allow cholesterol efflux when the NPC1 transporter is downregulated or mutated.