Ral and cathepsin A pathway links dietary cholesterol to loss of liver LDL receptors

Researchers at the University of California San Diego School of Medicine have identified a biological pathway through which a high-cholesterol diet gradually reduces the liver's capacity to clear LDL cholesterol from the blood. The pathway involves the protein Ral and the enzyme cathepsin A (CTSA), and blocking CTSA lowered circulating LDL in mice. The work, led by Alan Saltiel, is published in Nature.

How the liver clears LDL

The liver removes LDL cholesterol from the bloodstream using LDL receptors on the surface of its cells. These act as docking sites, capturing LDL particles and drawing them inside for processing. The more receptors are available, the more cholesterol the liver can remove.

This is the basis of two established drug classes. Statins and PCSK9 inhibitors both work, in different ways, by maintaining or increasing the number of LDL receptors. It has long been known that a diet rich in cholesterol impairs the liver's clearance of LDL, but the reason was not fully understood.

A pathway running from Ral to CTSA

Using experiments in mice and human cells, the team found that dietary cholesterol activates Ral, a protein Saltiel's group had earlier studied in fat cells. Higher Ral activity sets off a series of events that ends in the loss of LDL receptors, leaving fewer available to take up LDL from the blood.

The researchers then identified CTSA as a key component of this process. When they treated mice with a small-molecule inhibitor of the enzyme, LDL receptors became more stable and circulating LDL fell substantially. The title of the paper describes the mechanism as a Ral-dependent pathway driving turnover of the LDL receptor (LDLR).

Importantly, this route is distinct from the targets of current lipid-lowering drugs. That raises the possibility of a treatment for people who cannot reach safe LDL levels with existing therapies, or who cannot tolerate them because of side effects.

An inhibitor that has already been through Phase 1

A CTSA inhibitor was previously developed as a possible treatment for heart failure. That programme was discontinued for strategic reasons, but the compound had completed a Phase 1 trial in which its safety in humans was evaluated. The authors suggest it could move directly into a Phase 2 trial to test whether it lowers cholesterol in patients, which would avoid some of the years normally needed to find and vet a suitable compound.

Saltiel described the compound as an experimental drug already shown to be safe in humans, and said the group hopes to test its effectiveness in a clinical trial.

Limitations and next steps

The findings are at an early stage. The cholesterol-lowering effect of CTSA inhibition has been shown in mice, and the drug has not yet been shown to lower cholesterol in people. Safety data from a Phase 1 trial, which typically involves a small number of participants and a different condition, do not guarantee that the drug will be tolerated or effective when used for hypercholesterolaemia, possibly over long periods.

Several questions remain for researchers in lipid biology and pharmacology:

• How closely the mouse pathway is mirrored in human liver, beyond the evidence from human cell experiments.
• Whether CTSA inhibition adds benefit when combined with statins or PCSK9 inhibitors.
• What the effects of long-term CTSA inhibition are on other tissues, given the enzyme's wider roles.

A Phase 2 trial would be the first test of whether the mechanism translates into lower LDL in patients. The study was partly funded by the National Institutes of Health and an American Diabetes Association postdoctoral fellowship, and included co-authors from UC San Diego, the University of California San Francisco, the University of Texas Health Science Center at San Antonio and the University of Utah.

Source: Scientists discover a hidden driver of high cholesterol and a way to stop it (ScienceDaily: health and medicine, 1 November 2026).

Image: AI-generated illustration.