Scientists have uncovered a previously hidden biological mechanism that explains how high-cholesterol diets undermine the liver's ability to clear bad cholesterol from the bloodstream, and have identified a drug candidate that could offer a new treatment option for patients who cannot tolerate statins.
Breakthrough in Cholesterol Research
Researchers from the University of California San Diego School of Medicine have revealed how elevated cholesterol dismantles the liver's natural defences. The study, published in the journal Nature, was conducted using a combination of mice and human cells. It uncovered a mechanism that gradually reduces the number of LDL receptors on liver cells, which are crucial for removing low-density lipoprotein (LDL) or 'bad' cholesterol from the blood.
Study senior author Professor Alan Saltiel said: '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. This new discovery explains a critical piece of that puzzle.'
How the Mechanism Works
The liver is the primary organ responsible for extracting cholesterol from the blood. LDL receptors on the surface of liver cells act like docking stations, grabbing LDL cholesterol from the bloodstream and pulling it inside the cell for processing. The more LDL receptors present, the more cholesterol is cleared. Existing drugs like statins and PCSK9 inhibitors work by preserving or increasing the number of these receptors.
The new study found that a protein called Ral, previously studied in fat cells, is activated by high levels of dietary cholesterol. This activation triggers a process that depletes LDL receptors, ultimately relying on an enzyme called cathepsin A (CTSA).
Potential New Treatment
The team discovered that blocking CTSA with a small molecule inhibitor stabilised LDL receptors and 'dramatically lowered' circulating LDL cholesterol in mice. Professor Saltiel said: 'There's still a real need for new cholesterol-lowering options, since some people can't get to safe levels even with the drugs we have now. This new pathway we discovered is completely separate from anything that existing drugs target, so it gives us a new opportunity to fill that gap.'
Remarkably, a CTSA inhibitor has already progressed through early-stage drug development. Originally intended as a treatment for heart failure, it advanced to a Phase 1 clinical trial where it was deemed safe for humans, but was shelved for strategic reasons. Professor Saltiel believes the drug is now ready to be tested in a Phase 2 trial targeting high cholesterol. He added: 'Luckily, there's an experimental drug sitting on the shelf that's already been shown to be safe in humans. We hope to test whether this might be effective by conducting a clinical trial - which could potentially bring a new treatment option to patients much sooner than would have been expected.'
Implications for Patients
Heart disease linked to cholesterol remains the world's leading cause of death. While doctors have more treatment options than ever, including statins, many patients struggle to reach safe cholesterol levels or cannot tolerate side effects such as muscle pain. In the UK, doctors commonly prescribe Atorvastatin (Lipitor) and Simvastatin (Zocor), with other options like Fluvastatin, Rosuvastatin, and Pravastatin available. This new discovery could provide an alternative for those who do not respond well to existing medications.
