Hidden pathway could be targeted to reduce heart disease
A hidden biological pathway could be targeted to reduce cholesterol-related heart disease, research shows.
A team from the University of California San Diego School of Medicine uncovered a biological pathway involving the liver, explaining why high-cholesterol diets impede the body’s ability to clear harmful low-density lipoprotein (LDL) cholesterol from the blood.
The liver is the main organ involved in removing cholesterol from the blood so it can be broken down and used elsewhere. This is done through LDL receptors, which sit on the surface of liver cells and act like docking stations, grabbing LDL cholesterol from the bloodstream and pulling it inside the cell for processing.
The new research, carried out in a combination of mice and human cells, reveals a previously unknown mechanism that works against the cholesterol removal process, slowly reducing the number of LDL receptors and contributing to high blood cholesterol.
This process begins when a protein called Ral —previously studied in fat cells — is activated by high dietary cholesterol. The more Ral is activated, the fewer LDL receptors remain available to clear cholesterol from the blood.
“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, 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.”
Investigational drug already trialled in Phase I study
According to the study, the depletion of LDL receptors relies on an enzyme called cathepsin A (CTSA). By blocking CTSA with a small molecule inhibitor, the number of LDL receptors was stabilised and dramatically lowered circulating LDL cholesterol in mice.
The findings pave the way for drug development to bolster the liver’s defences, but drug development often takes additional research. However, a CTSA inhibitor has already been through the early stages of drug development, with the initial goal of treating heart failure.
The drug had previously been advanced to a Phase I clinical trial, where it was successfully tested for safety. This new discovery suggests that the investigational drug is already ready for testing in a Phase II trial for high cholesterol.
“Luckily, there’s an experimental drug sitting on the shelf that’s already been shown to be safe in humans,” Saltiel added.
“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.”