A newly identified liver pathway could offer a treatment target for people who cannot reach safe cholesterol levels with existing medicines, though a drug aimed at it has yet to be shown to lower cholesterol in humans.
Researchers at the University of California San Diego School of Medicine found that high dietary cholesterol activates a protein called Ral, setting off a process involving the enzyme cathepsin A, or CTSA, that leads to the loss of LDL receptors from liver cells.
Those receptors sit on the surface of liver cells, where they capture low-density lipoprotein, or LDL, cholesterol from the bloodstream and bring it inside for processing. The liver regulates blood cholesterol in part by taking up harmful cholesterol and eliminating it through processing and excretion.
Scientists had long known that cholesterol-rich diets reduce the liver's ability to clear cholesterol from blood, without fully understanding the mechanism. Alan Saltiel, a professor of medicine at UC San Diego School of Medicine and director of the UC San Diego/UCLA Diabetes Research Center, said the finding fills in part of that missing explanation.
Saltiel 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. This new discovery explains a critical piece of that puzzle.”
The work, published in Nature, used experiments in mice and human cells. Its authors include Saltiel, Xue Feng and Shuo Zhang.
In mice, scientists used a small-molecule inhibitor to block CTSA. LDL receptors became more stable and circulating LDL cholesterol fell dramatically.
The pathway differs from the mechanisms targeted by statins and PCSK9 inhibitors. Saltiel said that distinction could matter for patients whose cholesterol remains above safe levels despite available medicines.
Saltiel 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. 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.”
A CTSA-inhibiting drug had previously been developed as a possible treatment for heart failure. It passed a Phase 1 clinical trial that evaluated its safety in humans, although its development programme was halted for strategic reasons.
Saltiel said the team hopes a clinical trial can test whether the drug might lower cholesterol. “Luckily, there's an experimental drug sitting on the shelf that's already been shown to be safe in humans. 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.”
Cardiac disease associated with high cholesterol remains the leading cause of death worldwide.
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