Mechanism of LDL receptor loss identified in the US — ScienceDaily

Researchers at the University of California San Diego have identified a biological mechanism through which a high-cholesterol diet gradually weakens the liver’s ability to clear low-density lipoproteins (LDL) from the blood. In experiments on mice, blocking this mechanism stabilized LDL receptors and significantly reduced blood LDL levels, ScienceDaily reports.

The role of liver receptors

The liver clears cholesterol from the blood using LDL receptors on the surface of its cells. They capture LDL from the bloodstream and transport it inside the cells for further processing. The more such receptors are available, the more effectively the body can remove LDL from the blood.

Scientists found that a large amount of cholesterol in the diet activates the Ral protein. This triggers a sequence of processes that leads to the loss of LDL receptors in liver cells. The team also identified the role of the enzyme cathepsin A, or CTSA, which contributes to the process of reducing the number of these receptors.

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A candidate for clinical trials

The researchers used a small molecule, a CTSA inhibitor, and recorded stabilization of LDL receptors and a sharp reduction in circulating LDL in mice. Experiments were also conducted on human cells, but cholesterol reduction in humans with this drug has not yet been demonstrated.

The CTSA inhibitor had previously been developed as a potential treatment for heart failure. The program was later discontinued for strategic reasons, but the drug had already completed the first phase of clinical trials, during which its safety for humans was assessed. The study’s authors believe this could accelerate the transition to the second phase of research into the drug’s effectiveness against high cholesterol.

The study results were published in the journal Nature. According to the study’s senior author, Professor of Medicine Alan Saltiel, the identified pathway differs from the mechanisms targeted by statins and PCSK9 inhibitors.