Heart disease remains the leading cause of death worldwide, and high LDL cholesterol is one of its biggest risk factors.
LDL is often called “bad” cholesterol because too much of it can build up inside arteries, forming plaques that narrow blood vessels and increase the risk of heart attacks and strokes.
Although medicines such as statins and PCSK9 inhibitors have helped millions of people lower cholesterol, some patients still cannot reach healthy cholesterol levels or cannot tolerate the side effects.
Researchers are therefore searching for new ways to lower LDL cholesterol.
A new study from the University of California San Diego School of Medicine, published in Nature, has uncovered a previously unknown biological pathway that helps explain why eating a diet high in cholesterol reduces the liver’s ability to remove LDL cholesterol from the bloodstream.
The discovery also points to a possible new treatment that may reach patients faster because an experimental drug has already completed an early human safety trial.
The liver plays the central role in clearing LDL cholesterol from the blood. Liver cells contain LDL receptors that act like tiny docking stations. They capture LDL particles and pull them into the liver, where the cholesterol can be broken down or reused. The more LDL receptors a person has, the more LDL cholesterol can be removed from the bloodstream.
The research team found that a protein called Ral becomes more active when dietary cholesterol is high. Once activated, Ral starts a chain of events that reduces the number of LDL receptors on liver cells. With fewer receptors available, less LDL cholesterol is removed from the blood, allowing harmful cholesterol levels to rise.
The scientists also identified another important player, an enzyme called cathepsin A, or CTSA. In experiments using mice and human cells, blocking CTSA helped protect LDL receptors from being destroyed. As a result, the animals had much lower LDL cholesterol levels.
An especially exciting part of the discovery is that a CTSA-blocking drug already exists. It was originally developed for heart failure and successfully completed a Phase I clinical trial showing that it appeared safe in humans.
Although development later stopped for business reasons, the new findings suggest the same drug could now be tested as a treatment for high cholesterol in Phase II clinical trials.
The findings are important because this newly discovered pathway is different from the biological targets of today’s cholesterol medicines. If future studies confirm the results, the drug could provide another treatment option for people who cannot reach recommended cholesterol levels with existing therapies.
However, this research is still at an early stage. Most of the biological experiments were performed in mice and laboratory-grown human cells. Researchers still need larger clinical trials to determine whether blocking CTSA safely lowers cholesterol and reduces heart attacks or strokes in people.
Even if successful, healthy eating, regular exercise, and prescribed cholesterol medicines will continue to play essential roles in protecting heart health. Overall, the study opens an exciting new direction for cholesterol research and could eventually expand treatment choices for millions of patients.
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