New clues to why bad cholesterol can’t be lowered! Study reveals blockage in liver clearance mechanism

A high-cholesterol diet may not only increase cholesterol intake but also impair the liver's ability to remove bad cholesterol from the blood. US research has found that dietary cholesterol sets in motion a biological pathway that makes it easier for receptors on the surface of liver cells responsible for removing bad cholesterol to be broken down. In experiments on mice, researchers found that after blocking the key enzyme in this pathway, bad cholesterol in the blood dropped, providing a direction for the development of new blood lipid-lowering drugs.

The science news website "SciTechDaily" reported that this research was conducted by a team at the University of California, San Diego School of Medicine, and the paper was published in "Nature" on June 24. The liver uses low-density lipoprotein receptors on the cell surface to capture low-density lipoproteins in the blood, commonly known as bad cholesterol, and then brings them into cells for processing. Existing blood lipid-lowering drugs, such as statins and PCSK9 inhibitors, can also help lower blood cholesterol by maintaining or increasing the action of these receptors.

The research team found that a high-cholesterol diet activates specific proteins in the body, causing the receptors on the surface of liver cells responsible for clearing bad cholesterol to be "pulled" into the cells and handed over to an enzyme called cathepsin A (CTSA) for decomposition. When the cleaning tools are damaged, cholesterol cannot be lowered. But in experiments on mice, researchers could successfully preserve these receptors and reduce bad cholesterol in the blood as long as they used inhibitors to block the effects of CTSA.

The study also analyzed human genetic data and found that genetic variations in related pathways are related to cholesterol differences, but this does not mean that blocking this pathway has been proven to reduce human cholesterol.

The research team also pointed out that a drug candidate originally developed for heart failure entered Phase 1 human clinical trials and underwent preliminary safety evaluation, but was later stopped due to strategic considerations. The researchers hope to evaluate whether the drug can be adapted to treat high cholesterol, but its cholesterol-lowering effect still needs to be confirmed in human clinical trials.