Scientists have achieved a major milestone in figuring out how ‘bad’ cholesterol, known as low-density lipoprotein cholesterol (LDL-C), accumulates in our bodies. For the first time, researchers have demonstrated how the primary structural protein of LDL attaches to its receptor, a critical step that initiates the removal of LDL from the bloodstream, and explored the consequences when this process fails.
Researchers at the National Institute of Health (NIH) have made a significant discovery about how “bad” cholesterol, referred to as low-density lipoprotein cholesterol (LDL-C), accumulates in the body. For the first time, they have illustrated how the main structural protein of LDL connects to its receptor, which is the crucial first step in clearing LDL from the blood. They also investigated what occurs when this process is disrupted.
The results, published in Nature, enhance our comprehension of how LDL contributes to heart disease, which is the leading cause of death globally. This research could pave the way for customizing LDL-lowering medications like statins, potentially increasing their effectiveness.
“LDL is a key factor in cardiovascular diseases that claim a life every 33 seconds; thus, to comprehend this enemy, we must understand its nature,” stated Alan Remaley, M.D., Ph.D., co-senior author of the study and head of the Lipoprotein Metabolism Laboratory at NIH’s National Heart, Lung, and Blood Institute.
Up until now, scientists have struggled to visualize LDL’s structure, especially its interaction with LDLR, the receptor protein. Usually, when LDL attaches to LDLR, the process to remove LDL from the blood kicks off. However, genetic mutations can disrupt this process, leading to LDL accumulation in the blood and the formation of plaques in arteries, which can result in atherosclerosis and, ultimately, heart disease.
In the current study, researchers utilized advanced technology to visualize critical stages of this interaction and observed LDL from a fresh perspective.
“LDL is large and varies greatly in size, making it a complex subject,” explained Joseph Marcotrigiano, Ph.D., chief of the Structural Virology Section at NIH’s National Institute of Allergy and Infectious Diseases and co-senior author of the study. “We’ve achieved a level of detail unprecedented in this research area, allowing us to decipher its functions within the body.”
Employing high-resolution imaging through cryo-electron microscopy, the researchers captured the complete structural protein of LDL as it bound to LDLR. Additionally, they utilized artificial intelligence-driven software for protein modeling, enabling them to identify the structural locations of known genetic mutations associated with increased LDL levels. The creators of this software, who were not involved in the study, recently received the 2024 Nobel Prize in Chemistry.
The investigators discovered that numerous mutations connected to the area where LDL interacts with LDLR were related to a genetic condition called familial hypercholesterolemia (FH). This inherited disorder impairs the body’s ability to absorb LDL into cells, leading to extremely high LDL levels in affected individuals, who can suffer heart attacks at a young age. The study revealed that FH-related variants tended to cluster in specific areas of LDL.
These findings may help develop targeted treatments aimed at remedying dysfunctional interactions caused by mutations. Moreover, the researchers believe this knowledge can also aid individuals without genetic mutations who experience high cholesterol and are currently using statins, as these medications work by increasing LDLR in cells. By precisely understanding how LDLR interacts with LDL, they may design new drugs focused on these connection points to effectively reduce LDL levels in the bloodstream.
