Researchers Uncover Why High-Cholesterol Diets Weaken the Liver's Ability to Clear LDL

What if a hidden molecular pathway is preventing the liver from clearing harmful cholesterol, even when existing treatments are available? Scientists have identified a previously unknown mechanism that reduces the body's ability to remove LDL cholesterol from the bloodstream, along with an experimental drug that could potentially block this process.

Published in the journal Nature, the study conducted by researchers at the University of California San Diego School of Medicine investigated how high-cholesterol diets affect the liver's ability to regulate blood cholesterol levels.

The liver normally removes LDL, commonly known as bad cholesterol, through specialised proteins called LDL receptors. These receptors capture circulating cholesterol and transport it into liver cells for processing.

Researchers discovered that diets high in cholesterol activate a protein called Ral, triggering a biological pathway that reduces the availability of LDL receptors.

As receptor levels decline, the liver becomes less efficient at removing LDL cholesterol from circulation, potentially contributing to elevated blood cholesterol levels.

Importantly, researchers identified an enzyme called cathepsin A (CTSA) as a key component of this pathway.

Using experiments involving mice and human cells, scientists found that blocking CTSA with an experimental inhibitor helped stabilise LDL receptors.

The treatment also produced substantial reductions in circulating LDL cholesterol levels in mice.

Researchers suggested that this pathway differs from those targeted by commonly prescribed cholesterol-lowering medications, including statins and PCSK9 inhibitors.

Interestingly, a drug designed to inhibit CTSA had previously undergone Phase 1 clinical safety testing in humans during its development as a potential heart failure treatment.

This could provide a starting point for future clinical trials investigating whether the medication can effectively lower cholesterol.

However, researchers emphasised that the cholesterol-lowering effects have so far been demonstrated in preclinical experiments, and the drug has not been proven effective for treating high cholesterol in humans.

REFERENCE: Xue Feng, et al.; Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover. Nature, 2026; 656 (8127): 452 DOI: 10.1038/s41586-026-10697-z