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Researchers at UC San Diego report a biological pathway through which high dietary cholesterol can reduce liver LDL receptors, based on experiments in mice and human cells. Blocking the enzyme CTSA lowered circulating LDL in mice, while a drug that inhibits CTSA has previously passed a Phase 1 safety trial; it has not been shown to lower cholesterol in people.
Researchers at the University of California San Diego have identified a pathway that may help explain how a high-cholesterol diet weakens the liver’s ability to remove LDL cholesterol from the blood. In experiments with mice and human cells, blocking the enzyme CTSA stabilized LDL receptors and sharply lowered circulating LDL in mice; a CTSA-inhibiting drug has passed an earlier human safety trial, but has not been shown to lower cholesterol in people.
The study, published in Nature, describes a chain of biological events involving the protein Ral and the enzyme cathepsin A (CTSA). The researchers report that high dietary cholesterol activates Ral, setting off a process that reduces the number of LDL receptors on liver cells. With fewer receptors available, the liver has less capacity to take LDL out of circulation.
LDL receptors act as docking points on liver cells, capturing LDL particles so they can be taken up and processed. Existing treatments, including statins and PCSK9 inhibitors, help maintain or increase receptor availability through mechanisms different from the pathway described in this study. The researchers say that distinction could offer another target for people whose cholesterol remains high despite current medicines or who have difficulty taking them.
When the team used a small-molecule inhibitor to block CTSA, LDL receptors became more stable and circulating LDL fell substantially in mice. The report does not provide evidence that the same outcome has occurred in human patients. The experimental drug under consideration was developed for a potential heart-failure treatment and previously completed a Phase 1 trial assessing safety; that prior testing is not evidence that it is effective against high cholesterol.
A Possible Target Beyond Current Drugs
The findings point to a possible route for addressing a limitation of current cholesterol treatment: some patients do not reach recommended LDL levels with available medicines, while others experience side effects that make treatment difficult. Because the reported Ral-CTSA pathway differs from targets of commonly used drugs, it could eventually support a treatment approach that works alongside or separately from existing options.
That possibility remains prospective. The strongest treatment result described in the study is from mice, and the work in human cells does not establish that inhibiting CTSA will safely or effectively lower cholesterol in people. A human efficacy trial would need to test whether the biological effect translates into a meaningful change in blood LDL and whether the drug’s risks are acceptable for this use.
The previously tested compound may make further research more practical than starting with an entirely new drug, since it has already undergone an initial human safety assessment. But repurposing it would still require additional clinical evaluation, including assessment of dosing, side effects and benefit in people with high cholesterol.
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How Liver Receptors Shape LDL Levels
The liver helps regulate cholesterol by removing LDL from the bloodstream. Its LDL receptors capture LDL particles and bring them into liver cells for processing. The number and stability of those receptors affect how much LDL the liver can clear.
According to senior author Alan Saltiel, the effect of a high-cholesterol diet on the liver’s ability to clear blood cholesterol was known, but the process behind that effect was not fully understood. The new study identifies Ral and CTSA as parts of a mechanism that can reduce receptor availability. The researchers say this pathway is separate from the mechanisms targeted by statins and PCSK9 inhibitors.
The report says a CTSA inhibitor had previously been developed for possible heart-failure treatment, then left on the shelf after that program was discontinued for strategic reasons. It had completed a Phase 1 safety trial. The researchers propose that this history could allow the compound to move toward a Phase 2 study of effectiveness for cholesterol, subject to the necessary research and approvals.
“This new discovery explains a critical piece of that puzzle.”
— Alan Saltiel, senior author and UC San Diego professor of medicine
Human Benefits Remain Untested
The study does not show that the CTSA inhibitor lowers LDL in people. Its reported LDL reduction followed experiments in mice, and the prior Phase 1 trial assessed the drug’s safety in humans in an earlier development program, not its effectiveness against cholesterol.
It is not clear from the report when a Phase 2 study might start, whether the existing compound will be selected for one, or what dose and patient group researchers would study. The available source also does not provide detailed figures for the size or duration of the animal LDL reduction, or a full account of potential side effects. Those questions would need to be addressed in further research.
Clinical Testing Is the Next Test
The researchers say they hope to test the CTSA inhibitor in a clinical trial, potentially a Phase 2 study focused on whether it lowers cholesterol. The report does not confirm that such a trial has been approved, funded or opened to participants. Any clinical program would need to assess both effectiveness and safety for this new use, rather than relying on the earlier safety testing alone.
Until human results are available, the findings are a laboratory-stage advance and do not change current treatment recommendations. People taking cholesterol medication should not stop or change it based on this study; treatment decisions should be discussed with a health professional.
Key Questions
What pathway did the researchers identify?
The study reports that high dietary cholesterol activates the protein Ral, leading to a process involving CTSA that reduces LDL receptors on liver cells. Fewer receptors can limit the liver’s ability to remove LDL from the blood.
Did the CTSA inhibitor lower cholesterol in people?
No human cholesterol-lowering result is reported. The study found lower circulating LDL in mice; the drug’s earlier Phase 1 trial assessed safety, not its effectiveness against high cholesterol.
Why does the earlier Phase 1 trial matter?
The compound has already undergone an initial human safety assessment for a potential heart-failure use. That history may help researchers plan further testing, but it does not establish safety for every use or prove that the drug lowers LDL.
Could this replace statins or other current treatments?
That is not known. The researchers describe CTSA as a target separate from those used by statins and PCSK9 inhibitors, but the new approach has not yet been shown to work in people or compared with standard treatment in a clinical trial.
Source: sciencedaily.com
