Doctors have long known that diets rich in cholesterol can raise LDL cholesterol levels, but scientists have not fully understood why the liver gradually becomes less effective at clearing cholesterol from the blood.
A new study published in Nature by researchers at the University of California San Diego School of Medicine provides an important answer and may speed the development of a completely new cholesterol-lowering medicine.
The liver normally protects the body by removing LDL cholesterol from circulation. It does this using LDL receptors located on the surface of liver cells. These receptors grab LDL particles and carry them into the liver for processing. Many current cholesterol medicines work by increasing the number of these receptors or preventing their loss.
In the new study, researchers discovered a hidden signaling pathway that works in the opposite direction.
They found that high dietary cholesterol activates a protein called Ral. This protein then triggers processes that reduce the number of LDL receptors. With fewer receptors available, the liver cannot remove LDL cholesterol as efficiently, allowing cholesterol levels to climb.
The scientists traced this process to an enzyme known as CTSA. When they blocked CTSA using a small experimental drug, LDL receptors remained on liver cells for longer, and cholesterol levels dropped substantially in mouse studies. Laboratory experiments using human cells supported these findings.
One reason the discovery has attracted attention is that a CTSA inhibitor has already undergone Phase I clinical testing for another medical condition. The drug was found to be safe in healthy volunteers before the project was discontinued for strategic reasons.
Because early safety testing has already been completed, researchers hope that testing the medicine for high cholesterol could move forward more quickly than developing an entirely new drug.
The study addresses an important unmet medical need. Although statins and newer injectable medicines are highly effective for many people, some patients cannot tolerate them or still have dangerously high LDL cholesterol despite treatment.
A medicine targeting this newly discovered pathway could potentially be used alongside existing therapies to achieve better cholesterol control.
Despite the promising results, caution is still needed. The research has not yet shown that blocking CTSA prevents heart attacks or saves lives in patients. Future Phase II and Phase III clinical trials must determine whether the drug is both effective and safe when used over longer periods.
Researchers will also need to study which patients benefit most from this new approach.
Overall, the findings represent a major scientific advance because they reveal a previously unknown mechanism controlling cholesterol removal and identify an existing drug candidate that may accelerate the development of future treatments for cardiovascular disease.
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Source: University of California San Diego.
