Scientists discover a hidden driver of high cholesterol and a way to stop it
Scientists have uncovered a hidden mechanism that allows high-cholesterol diets to undermine the body's natural cholesterol defenses, and blocking it dramatically lowered harmful LDL cholesterol in mice. Even more promising, an experimental drug targeting this pathway has already passed an early human safety trial, potentially speeding the development of a new treatment for high cholesterol.
Key points
- UC San Diego researchers found a new biological pathway that reduces LDL receptors and raises cholesterol.
- Blocking the enzyme cathepsin A stabilized LDL receptors and sharply lowered LDL cholesterol in mice.
- An experimental CTSA inhibitor already tested for safety in humans could advance to a Phase 2 trial.
Researchers at the University of California San Diego School of Medicine have identified a previously unknown biological pathway that helps explain why high-cholesterol diets weaken the body's ability to remove LDL cholesterol from the blood. The findings were published in Nature.
The pathway involves a protein called Ral, which is activated by dietary cholesterol and sets off a chain of events that reduces the number of LDL receptors on liver cells. The researchers also identified an enzyme, cathepsin A (CTSA), that drives the depletion of these receptors.
How the mechanism works
Liver cells use LDL receptors to capture LDL cholesterol from the bloodstream and bring it inside for processing. More receptors allow the liver to clear more cholesterol. The newly discovered process reduces the number of available receptors over time.
In experiments with mice and human cells, the team found that high dietary cholesterol activates Ral, leading to fewer LDL receptors. When scientists used a small molecule inhibitor to block CTSA, LDL receptors became more stable and circulating LDL cholesterol dropped dramatically in mice.
We've known for a long time that a high-cholesterol diet reduces the liver's ability to clear cholesterol from the blood, but we didn't fully understand why
— Alan Saltiel
A drug already tested in humans
A drug designed to inhibit CTSA had previously been developed for heart failure and completed a Phase 1 clinical trial for safety in humans, though the program was discontinued. Researchers believe this existing inhibitor could move into a Phase 2 trial to test its effectiveness against high cholesterol.
The drug has not yet been shown to lower cholesterol in humans. Senior author Alan Saltiel said the newly identified pathway is separate from those targeted by current cholesterol medications, which could help patients who do not respond adequately to existing drugs.
