While some cholesterol is a healthy thing for properly functioning cells, too much of it can cause blockages in the arteries and heart trouble, along with a host of other negative health outcomes. Scientists have discovered a new mechanism by which a “bad” type of cholesterol gains entry to the cells, identifying a pair of proteins that work like an entry tunnel. These proteins show promise as new targets for drugs that could lower cholesterol levels in the blood to help prevent disease.
The discovery made by an international team of researchers was only possible thanks to advances in imaging technology that enabled them to inspect proteins at a near-atomic level. In this case, the team were investigating the role two proteins, NPC1 and NPC2, play in transporting low-density lipoprotein (LDL) cholesterol, often referred to as “bad” cholesterol, into our cells.
“Before 2013 we often had to theorise about how membrane proteins worked and how they functioned, but now we can actually see them, and seeing is believing,” says study author Prof Rob Yang from the UNSW in Australia. “We were able to look at the NPC1 and NPC2 proteins and see exactly the role they play in transporting this LDL cholesterol into the cell.”
Through these detailed observations, the team found that the two proteins work in tandem to welcome LDL cholesterol into the cells, enabling it to overcome the lysosomes that would normally act as a protective barrier. These lysosome structures feature a membrane that helps them break down and repel invaders, but the team found that the NPC1 and NPC2 proteins are what enables LDL cholesterol to slip through the cracks.
“If you imagine NPC2 bringing the cholesterol to the gate at the edge of the lysosome membrane, the NPC1 protein provides a tunnel for this cholesterol into the cell itself,” says Yang. “Cholesterol is an important building block for our cells, but too much of it in the blood can clog our arteries leading to heart disease. Now that we understand how it gets into the cell, we can work towards developing drugs that target the NPC1 and NPC2 proteins to facilitate its influx into cells so as to lower the amount of it in the blood.”
The NPC1 and NPC2 proteins are encoded by a pair of genes of the same name, so the value of this discovery might not just be limited to treating things like heart disease, but also conditions created by mutations in those genes. One of those is the often fatal Niemann-Pick disease type C in young children, in which the the mutated genes cause LDL cholesterol to build up in the lysosomes and lead to cell death.
“By sequencing the genes of people suffering from this disease you can see where the mutation occurs and then develop targeted medicines that restore the protein’s ability to transport the cholesterol,” says Yang.
The findings could also have ramifications for how we treat some viruses, with previous research demonstrating that Ebola also makes its way into the cells by binding with the NPC1 protein and avoiding the defenses of the lysosomes, as one example.
“Normally the acidic conditions in the lysosome break down foreign invaders,” says Yang. “But the Ebola virus latches on to the NPC1 protein and gets a free passage into the cell where it can then make lots of copies of itself and infect other cells. If we know this is the mechanism, we could develop drugs to block the Ebola virus from ‘shaking hands’ with the NPC1 protein, leaving the Ebola virus to be broken down by the lysosome’s acidic environment.”
The scientists also raise the possibility that a similar technique could be used to treat COVID-19 since, like Ebola, it is an RNA virus, though the connection to the NPC1 protein would need to be investigated through further studies.
The research was published in the journal Cell.
Source: University of New South Wales
