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UC San Diego researchers report that dietary cholesterol can activate a Ral–CTSA pathway that reduces LDL receptors in the liver, based on experiments in mice and human cells. Blocking CTSA lowered circulating LDL in mice; a related experimental drug has passed a Phase 1 safety trial but has not been shown to lower cholesterol in people.
Researchers at the University of California San Diego School of Medicine have identified a biological pathway through which dietary cholesterol may reduce the liver’s ability to remove LDL cholesterol, and found that blocking one part of the pathway lowered LDL in mice. The study, published in Nature, also points to an experimental drug that has undergone human safety testing, but it has not been shown to lower cholesterol in people.
In experiments involving mice and human cells, the team found that a protein called Ral becomes active in response to high dietary cholesterol. This sets off a chain of events involving the enzyme cathepsin A (CTSA), which contributes to the loss of LDL receptors on liver cells. Those receptors capture LDL from the blood so the liver can process it; fewer receptors can mean less capacity to clear LDL.
The researchers used a small-molecule inhibitor to block CTSA. In mice, the intervention made LDL receptors more stable and dramatically lowered circulating LDL cholesterol, according to the study report. The result is from animal research: the source does not report a cholesterol-lowering trial in people or provide a numerical effect size in the supplied material.
The team says the pathway differs from the targets of established treatments such as statins and PCSK9 inhibitors. A drug developed to inhibit CTSA was previously investigated for heart failure and completed a Phase 1 clinical trial that evaluated safety in humans. That development program was discontinued for strategic reasons, the report says. Its prior safety testing does not establish that it will reduce cholesterol or be safe and effective for this new use.
A Separate Route to Lower LDL
The finding may point to a treatment strategy that works through a different biological target from widely used cholesterol medicines. The researchers say that could matter for people who do not reach recommended cholesterol levels with existing drugs or who have difficulty taking them because of side effects. However, the study does not show that this approach helps those patients; that would require clinical testing.
The potential practical advantage is the availability of a compound with some prior human safety data. If researchers pursue it for cholesterol, that background could inform further development. It cannot substitute for trials testing the drug’s effects on LDL levels, dose, side effects and overall safety in the intended patient group.
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How the Liver Clears LDL
The liver helps regulate cholesterol by removing LDL from the bloodstream. LDL receptors on liver cells bind circulating LDL and bring it into the cells for processing. Treatments including statins and PCSK9 inhibitors help maintain or increase the availability of these receptors, though they act through pathways different from the one described in this study.
Researchers have long observed that diets high in cholesterol can impair the liver’s removal of cholesterol, but the mechanisms behind that effect have not been fully understood. The new work proposes a link from dietary cholesterol through Ral and CTSA to reduced receptor stability. It adds a possible explanation; it does not establish that this pathway is the sole cause of diet-related changes in LDL or that the findings translate directly to people.
“This new discovery explains a critical piece of that puzzle.”
— Alan Saltiel, senior author and professor of medicine at UC San Diego School of Medicine
Human Cholesterol Effects Remain Unknown
The evidence described so far comes from mice and human cells. Although the candidate drug previously completed a Phase 1 trial assessing safety in people, the report says it has not been tested in humans as a cholesterol treatment. It is not yet known whether blocking CTSA will lower LDL in patients, how large any effect might be, or what dose and risks would be involved.
The supplied report says the researchers believe the compound could potentially advance to a Phase 2 trial, but does not identify a trial start date, sponsor, recruitment plan or regulatory decision. The duration and persistence of any effect, and which patients might benefit, also remain undetermined.
Clinical Testing Would Be the Next Step
The next step described by Saltiel is a clinical trial to test whether the CTSA inhibitor can lower cholesterol in people. A Phase 2 study would be needed to examine its effectiveness and further characterize safety in the intended setting. No such trial is confirmed in the supplied report, and no timetable or enrollment details are provided.
Until human results are available, the findings are an early research lead rather than a new treatment option. Patients should not change prescribed cholesterol medicines based on the study; decisions about treatment should be made with a health professional.
Key Questions
What pathway did the researchers identify?
The study describes a pathway in which high dietary cholesterol activates Ral, followed by activity involving CTSA. In experiments, the process contributed to the loss of LDL receptors on liver cells.
Did blocking CTSA lower cholesterol in people?
No human cholesterol-lowering result is reported. The researchers said a CTSA inhibitor lowered circulating LDL in mice; the candidate drug’s earlier human trial assessed safety, not cholesterol treatment.
Is the experimental drug available as a cholesterol treatment?
No. The report describes it as an experimental drug, and it has not been shown to treat high cholesterol in people or approved for that use.
How might this approach differ from current medicines?
The researchers say the Ral–CTSA pathway is separate from the targets of statins and PCSK9 inhibitors. Whether that difference will provide a useful option for patients needs to be tested in clinical trials.
What happens next?
The researchers hope to test the candidate in a clinical trial. The source does not confirm that a Phase 2 trial has started or provide a schedule.
Source: sciencedaily.com
