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Researchers at UC San Diego report a pathway through which dietary cholesterol may reduce the liver’s supply of LDL receptors, limiting its ability to clear LDL from the blood. Blocking the enzyme CTSA lowered circulating LDL in mice, and a CTSA-targeting drug previously assessed for safety in a Phase 1 trial could be considered for further testing. It has not been shown to lower cholesterol in people.
Researchers at the University of California San Diego have identified a biological pathway that may help explain how a high-cholesterol diet reduces the liver’s ability to clear LDL cholesterol, and found that blocking a related enzyme lowered LDL in mice. The study, published in Nature, points to a possible treatment target distinct from existing cholesterol drugs, but the approach has not yet been shown to work in people.
In experiments using mice and human cells, the team found that dietary cholesterol activated a protein called Ral. The resulting chain of events involved cathepsin A (CTSA), an enzyme the researchers say contributes to the loss of LDL receptors on liver cells. Those receptors capture LDL from the bloodstream so the liver can process it.
When researchers used a small-molecule inhibitor to block CTSA, LDL receptors became more stable and circulating LDL levels dropped in mice, according to the report. The study describes this as a pathway separate from the targets of current cholesterol treatments. These findings are experimental: they do not establish that the same intervention will lower cholesterol or be safe and effective as a treatment in patients.
The researchers also pointed to a CTSA inhibitor previously developed as a potential heart-failure drug. It had undergone a Phase 1 safety trial in humans, but that trial did not test it as a cholesterol treatment. The drug development program was discontinued for strategic reasons, according to the report. The scientists say its prior testing may make further research possible sooner than starting with a new compound, while stressing that its effect on cholesterol in people remains unknown.
A Separate Target for LDL Reduction
The finding may offer a direction for research into people whose LDL remains high despite current medications, as well as those who have difficulty taking existing drugs. The proposed pathway is distinct from the mechanisms targeted by statins and PCSK9 inhibitors, which help maintain or increase the number of liver LDL receptors. A treatment that acts through CTSA could, if it proves effective and safe, add another approach rather than simply repeat those mechanisms.
That possibility is not yet a clinical benefit. The LDL reduction reported here occurred in mice; the study does not show that blocking CTSA lowers LDL in humans, prevents heart attacks, or improves other health outcomes. The previous Phase 1 safety assessment of the candidate drug also does not establish its safety for long-term use or its effectiveness for cholesterol. Further testing would be needed before doctors could consider it as a treatment.
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How the Liver Clears LDL
The liver helps regulate cholesterol by removing LDL from circulation. It does this in part through LDL receptors on liver cells, which bind LDL and bring it inside for processing. The number of functioning receptors affects how much LDL the liver can clear.
Common treatments, including statins and PCSK9 inhibitors, work in ways that help preserve or increase available receptors. The UC San Diego team’s work focuses on a different process: how Ral and CTSA may contribute to receptor loss after high dietary cholesterol exposure. The study addresses a possible mechanism behind impaired clearance; it does not replace established advice or treatments for managing cholesterol.
“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 Results Still Unknown
The central unresolved question is whether blocking CTSA can safely lower LDL in people. The reported experiments included mice and human cells, but the drug has not been tested as a cholesterol treatment in a human clinical trial. Its earlier Phase 1 study evaluated safety in a different development program, not its effect on LDL or cardiovascular risk.
The source does not provide details such as the size or duration of the animal experiments, the magnitude of the LDL change, or whether investigators have secured funding, regulatory clearance, or a trial site for a Phase 2 study. It is also not clear when clinical testing might begin. A candidate’s prior safety evaluation can inform further development, but it does not guarantee that later trials will confirm safety or effectiveness.
Clinical Testing Would Be the Next Step
The researchers say they hope to test the CTSA inhibitor in a clinical trial, potentially a Phase 2 study examining whether it affects cholesterol in people. The report describes this as a possibility, not a scheduled or active trial. Before any conclusions about treatment can be drawn, investigators would need human data on LDL response, dosing, safety and side effects.
Readers should watch for a formal trial announcement and its protocol, including who can participate, what outcomes it measures and how it compares the drug with existing care. Until such results are available, the finding remains a research lead rather than a new treatment option. People making decisions about cholesterol medication should consult a qualified health professional.
Key Questions
What pathway did the researchers identify?
The study links dietary cholesterol to activation of the protein Ral and a process involving the enzyme CTSA. In experiments, this process contributed to fewer LDL receptors on liver cells, which can reduce the liver’s capacity to remove LDL from the blood.
Did the CTSA inhibitor lower cholesterol in people?
No human cholesterol result is reported. Blocking CTSA lowered circulating LDL in mice; the candidate drug’s earlier Phase 1 trial assessed safety, not its effect on cholesterol.
Is the experimental drug available to patients?
No. The report describes the compound as an experimental candidate and says the researchers hope to test it in a clinical trial. It is not established as a cholesterol treatment.
How is this different from statins?
The researchers describe the Ral-CTSA pathway as distinct from targets of existing treatments, including statins and PCSK9 inhibitors. Whether a drug acting on CTSA can provide a useful additional option remains to be tested in people.
What happens next?
The research team hopes to pursue clinical testing, potentially in a Phase 2 trial. The supplied report does not confirm that a trial has been approved, launched or given a start date.
Source: sciencedaily.com
