University of California San Diego Researchers Identify Hidden Cholesterol Pathway
High cholesterol continues to drive heart disease as the leading cause of death worldwide, even as physicians rely on an expanding arsenal of treatments. Researchers at the University of California San Diego School of Medicine have now pinpointed a previously unknown biological pathway that explains why diets high in cholesterol gradually impair the liver’s ability to clear low-density lipoprotein (LDL) cholesterol from the bloodstream. Their findings, published in Nature, outline both the molecular mechanism behind receptor depletion and an experimental drug that could potentially target it.
“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,” said senior author Alan Saltiel, PhD, professor of medicine at UC San Diego School of Medicine and director of the UC San Diego/UCLA Diabetes Research Center. “This new discovery explains a critical piece of that puzzle.”
How Liver Cells Lose LDL Receptors Under Dietary Stress
To control circulating cholesterol, liver cells utilize surface proteins known as LDL receptors, which function as docking stations to capture harmful LDL particles and pull them inside for breakdown. When liver cells maintain a higher density of these receptors, the organ clears more cholesterol from the circulation. Widely prescribed medications such as statins and PCSK9 inhibitors achieve their therapeutic effects largely by preserving or increasing this receptor supply.
The newly identified pathway undermines this cleansing process through a distinct biological chain reaction. Experiments involving mice and human cells revealed that consuming high amounts of dietary cholesterol activates a protein named Ral, which Saltiel had previously studied in fat cells. As Ral activity increases, it triggers the depletion of LDL receptors, leaving fewer docking stations available on the cell surface.
The research team traced this receptor loss to an enzyme called cathepsin A (CTSA). When scientists administered a small molecule inhibitor to block CTSA, receptor stability improved significantly, and circulating LDL cholesterol levels dropped sharply in mice.
Advancing a Shelved CTSA Inhibitor to Human Clinical Trials
Translating a novel biological target into a viable pharmaceutical typically requires years of preliminary compound screening and safety validation. In this instance, however, researchers already have a candidate compound on hand. An experimental drug designed to inhibit CTSA was previously developed for heart failure and successfully cleared a Phase 1 clinical trial for human safety before the program was shelved for strategic reasons.
Because the compound has already passed initial safety evaluations in humans, investigators hope to advance the medication into a Phase 2 clinical trial to test its efficacy against high cholesterol. While the drug has not yet demonstrated cholesterol-lowering effects in patients, its existing safety data could accelerate the development timeline.
“Luckily, there’s an experimental drug sitting on the shelf that’s already been shown to be safe in humans,” said Saltiel. “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.”
Researchers note that this pathway operates entirely independently of the mechanisms targeted by existing statins or PCSK9 inhibitors. That separation could offer an alternative therapeutic avenue for patients who experience adverse side effects from current medications or fail to reach safe cholesterol targets.
Frequently Asked Questions About the UC San Diego Cholesterol Study
What specifically activates the newly discovered cholesterol-depleting pathway?
Consuming high amounts of dietary cholesterol activates a protein called Ral inside liver cells, which initiates a chain reaction leading to the loss of LDL receptors.
How does blocking cathepsin A affect cholesterol levels in laboratory testing?
When researchers used a small molecule inhibitor to block the enzyme cathepsin A (CTSA) in mice, it stabilized their LDL receptors and caused a dramatic drop in circulating LDL cholesterol.
Why might the experimental CTSA inhibitor reach human trials faster than typical new drugs?
The compound previously underwent a Phase 1 clinical trial to evaluate human safety as a potential heart failure treatment, allowing researchers to potentially advance the medication into a Phase 2 clinical trial.
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