Researchers at the University of California San Diego School of Medicine have identified a previously unknown biological mechanism that enables high-cholesterol diets to reduce the liver's ability to clear harmful LDL cholesterol from the blood, and they have found an experimental drug that may block this pathway and has already passed initial human safety testing.
The work, published in Nature, reveals a chain of events that reduces LDL receptors, the structures that capture and remove cholesterol from circulation. The number of these receptors matters for how much cholesterol the liver can remove from circulation.
The newly identified process begins with a protein called Ral, which the researchers found becomes activated by high dietary cholesterol. Ral activation sets off a sequence that reduces LDL receptor availability. An enzyme called cathepsin A (CTSA) was also found to drive this receptor-depletion process. When scientists used a small molecule inhibitor to block CTSA in mice, LDL receptors became more stable and circulating LDL cholesterol dropped dramatically.
"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."
The pathway is distinct from those targeted by current cholesterol medications, including statins and PCSK9 inhibitors, which work by maintaining or increasing LDL receptor numbers. This difference could offer treatment options for patients who do not respond adequately to existing drugs.
"There's still a real need for new cholesterol-lowering options, since some people can't get to safe levels even with the drugs we have now," said Saltiel. "This new pathway we discovered is completely separate from anything that existing drugs target, so it gives us a new opportunity to fill that gap."
The potential drug is a CTSA inhibitor originally developed for heart failure but discontinued for strategic reasons after progressing through a Phase 1 clinical trial, in which it was found safe in humans. The researchers believe it could be advanced into a Phase 2 trial to test its effectiveness against high cholesterol, potentially accelerating development of a new treatment.
"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."
The findings are at an early stage, and the drug has not yet been shown to lower cholesterol in humans.
Analysis
Why This Matters
- Heart disease linked to high cholesterol remains the leading cause of death worldwide, and many patients cannot reach safe cholesterol levels with current treatments or experience side effects.
- The newly identified pathway is separate from those targeted by statins and PCSK9 inhibitors, offering a potential new mechanism for lowering cholesterol.
- Because an experimental drug targeting this pathway has already passed human safety testing, a clinical trial could begin sooner than typical for a new discovery, potentially shortening the path to a new therapy.
Background
Cholesterol-lowering drugs such as statins and PCSK9 inhibitors work by increasing the number of LDL receptors on liver cells, which capture and clear cholesterol from the blood. The liver's ability to clear cholesterol is central to controlling blood cholesterol levels. Despite these treatments, many patients still have high cholesterol.
Key Perspectives
Alan Saltiel, senior author (UC San Diego): called the discovery "a critical piece of that puzzle" explaining why a high-cholesterol diet weakens the liver's cholesterol clearance. He noted the new pathway is "completely separate from anything that existing drugs target" and provides "a new opportunity to fill that gap" for patients who cannot reach safe levels. He also said the experimental drug being safe in humans could "potentially bring a new treatment option to patients much sooner than would have been expected."
What to Watch
- Whether the CTSA inhibitor advances to a Phase 2 clinical trial to test its cholesterol-lowering effectiveness in humans.
- If the drug proves effective, how it compares to existing treatments for patients who do not respond to statins or PCSK9 inhibitors.
- Whether the Ral-dependent pathway identified in mice and human cells will prove to be the same driver of high cholesterol in patients.
Checked
12 claims in this story checked against 1 source: 12 supported.
Show each claim
- SupportedScientists have identified a hidden driver of high cholesterol and a possible way to stop it.Latest Science News -- ScienceDaily: “Scientists have discovered a hidden driver of high cholesterol and a promising way to block it using an experimental drug already tested for safety in humans.”
- SupportedResearchers say an experimental drug already tested for safety in humans may target the newly discovered pathway.Latest Science News -- ScienceDaily: “they have identified an experimental drug that has already undergone safety testing in humans and could potentially interfere with this process.”
- SupportedUC San Diego researchers identified a previously unknown mechanism by which high-cholesterol diets weaken the liver’s ability to remove LDL cholesterol from the blood.Latest Science News -- ScienceDaily: “Researchers at the University of California San Diego School of Medicine have now identified a previously unknown biological pathway that helps explain why diets high in cholesterol can gradually weaken the body's ability to remove harmful low-density lipoprotein (LDL) cholesterol from the bloodstream.”
- SupportedThe experimental drug has already passed initial human safety testing.Latest Science News -- ScienceDaily: “the experimental medication had already progressed through a Phase 1 clinical trial, where it was successfully evaluated for safety in humans.”
- SupportedSaltiel said, “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,” and “This new discovery explains a critical piece of that puzzle.”Latest Science News -- ScienceDaily: “"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."”
- SupportedHigh dietary cholesterol activates Ral, setting off a chain of events that leads to the loss of LDL receptors.Latest Science News -- ScienceDaily: “The team discovered that consuming high amounts of dietary cholesterol activates Ral, setting off a chain of events that leads to the loss of LDL receptors.”
- SupportedThe researchers found that CTSA helps drive the process that depletes LDL receptors.Latest Science News -- ScienceDaily: “The researchers then identified another critical piece of the mechanism: an enzyme called cathepsin A (CTSA). This enzyme helps drive the process responsible for depleting LDL receptors.”
- SupportedBlocking CTSA with a small-molecule inhibitor stabilized LDL receptors and dramatically lowered circulating LDL cholesterol in mice.Latest Science News -- ScienceDaily: “When scientists used a small molecule inhibitor to block CTSA, the results were striking. LDL receptors became more stable, and levels of circulating LDL cholesterol dropped dramatically in mice.”
- SupportedSaltiel said, “There's still a real need for new cholesterol-lowering options, since some people can't get to safe levels even with the drugs we have now,” and that the new pathway is separate from existing drug targets.Latest Science News -- ScienceDaily: “"There's still a real need for new cholesterol-lowering options, since some people can't get to safe levels even with the drugs we have now," said Saltiel. "This new pathway we discovered is completely separate from anything that existing drugs target, so it gives us a new opportunity to fill that gap."”
- SupportedResearchers believe the existing CTSA inhibitor could advance to a Phase 2 trial to test its effectiveness against high cholesterol.Latest Science News -- ScienceDaily: “researchers believe the existing CTSA inhibitor may be ready to advance into a Phase 2 clinical trial to investigate its effectiveness against high cholesterol.”
- SupportedThe drug has not yet been shown to lower cholesterol in humans.Latest Science News -- ScienceDaily: “The findings are still at an early stage, and the drug has not yet been shown to lower cholesterol in humans.”
- SupportedSaltiel said, “Luckily, there's an experimental drug sitting on the shelf that's already been shown to be safe in humans,” and “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.”Latest Science News -- ScienceDaily: “"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."”