"Bad" cholesterol is a leading cause of cardiovascular disease, which kills one person every 33 seconds in the United States," laments Alan Remaley, a researcher at the American Heart, Lung and Blood Institute. "And to defeat your enemy, you must first know what he looks like." In a new study, he has drawn a more precise portrait of LDL, also called "bad" cholesterol, and in particular of a small protein essential for its absorption by the liver. Discoveries that could well open a new therapeutic avenue. Their results were published in the journal Nature.
Understanding “good” and “bad” cholesterol transporters
Good and bad cholesterol is a bit like the story of Dr. Jekyll and Mr. Hyde. There is only one cholesterol, essential to our body, but its effect depends on the transporter it uses. LDL lipoproteins, nicknamed "bad cholesterol", distribute cholesterol from the liver to the cells. In excess, they risk aggregating on the walls of blood vessels, and promoting the formation of atheromatous plaques, a risk factor for cardiovascular diseases. Conversely, HDL, or "good cholesterol," acts as garbage collectors: it brings excess cholesterol back to the liver so that it can be recycled or eliminated," simplifies Alan Remaley, during an interview for Science and Future. This two-way transport system is crucial for lipid balance. So what's going wrong in people with high cholesterol? The uptake of cholesterol into liver cells.
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Normally, LDL binds to a receptor on the liver cell membrane, called LDLR. The cell membrane then deforms, creating a small cavity to accommodate the cholesterol, until it is completely included in the cell, thanks to a vesicle. This is called endocytosis. This vesicle transports the LDL and its receptor inside the cell. Once in the cell, the vesicle fuses with a compartment called an endosome. The acidity of the endosome causes the LDL to dissociate from its receptor, which is then recycled to the cell surface for reuse, while the cholesterol contained in the LDL is used to make essential substances, such as bile acids, or eliminated.
A binding defect causing hypercholesterolemia
But in people with familial hypercholesterolemia, the binding between LDL and its receptor on the surface of the liver cell is lacking. Why? Several scenarios are possible, but often these patients have a genetic abnormality of the LDL receptor or the protein that binds to the receptor, called "apolipoprotein B.", " explains the researcher.
Previous research had revealed how mutations in the gene linked to the receptor lead to misfolding and dysfunction. In their new work, the researchers now shed light on how different mutations in the apolipoprotein B gene can result in a different conformation of the protein and thus interfere with the ability of LDL to bind to the receptor.
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Direct consequence: LDL is not properly integrated by liver cells, and remains in the blood, leading to hypercholesterolemia. The main risk for people who suffer from it is the deposits of LDL on the walls of blood vessels because they can lead to atherosclerosis, the underlying cause of coronary heart disease which can lead to a myocardial infarction," he adds.
Scientists now have fundamental details about how bad cholesterol binds to liver cells, a crucial step in removing it from the blood. This discovery also reveals the consequences of impaired LDL-receptor binding, as occurs in patients with high cholesterol. "With this new knowledge, we have refined our understanding of cholesterol-lowering drugs, such as Statins, and we hope to eventually be able to design new treatments that specifically target the parts we have identified,” Alan Remaley, concluding remarks
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