Heart disease related to high cholesterol remains the leading cause of death worldwide. Although doctors have more treatment options than ever, many people still struggle to lower their cholesterol to safe levels. Others experience side effects that make it difficult to take existing medications. Researchers at the University of California, San Diego School of Medicine have identified a previously unknown biological pathway that helps explain why high-cholesterol diets can gradually weaken the body’s ability to remove harmful low-density lipoprotein (LDL) cholesterol from the bloodstream. Even more promising is that they have identified an experimental drug that has already undergone safety testing in humans and could potentially interfere with this process. The findings, published in Nature, could open the door to a new approach to treating high cholesterol. “We have known for a long time that a high-cholesterol diet reduces the liver’s ability to remove 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 fundamental piece of that puzzle.” How the Liver Eliminates Bad Cholesterol The liver plays a central role in controlling cholesterol levels. It removes cholesterol from the bloodstream so it can be processed, broken down, and used by other parts of the body. To achieve this, liver cells rely on structures called LDL receptors. Located on the surface of these cells, the receptors function much like docking stations, capturing LDL cholesterol circulating in the blood and bringing it inside for processing. The number of receivers available is important. When liver cells have more LDL receptors, they can remove more cholesterol from circulation. This is one reason why widely used cholesterol medications, including statins and PCSK9 inhibitors, are effective. They help maintain or increase the number of receptors available to eliminate LDL cholesterol. Scientists discover hidden cholesterol pathway Using experiments with mice and human cells, researchers discovered a previously unrecognized process that interferes with the liver’s ability to remove cholesterol. Over time, this mechanism reduces the number of LDL receptors, making it harder for the body to keep blood cholesterol under control. The process begins with a protein known as Ral, which Saltiel had previously investigated in fat cells. The team found that consuming large amounts of dietary cholesterol activates Ral, triggering a chain of events that leads to the loss of LDL receptors. As Ral activity increases, fewer receptors remain available to remove harmful cholesterol from the bloodstream. The researchers then identified another critical piece of the mechanism: an enzyme called cathepsin A (CTSA). This enzyme helps boost the process responsible for LDL receptor depletion. When scientists used a small molecule inhibitor to block CTSA, the results were surprising. LDL receptors became more stable and circulating LDL cholesterol levels decreased dramatically in mice. The discovery is especially significant because the newly identified pathway is different from those targeted by current cholesterol drugs. That distinction could allow treatments to be developed for patients who do not respond adequately to existing medications. “There is still a real need for new options to lower cholesterol, as some people cannot reach safe levels even with the medications we have now,” Saltiel said. “This new pathway we discovered is completely separate from anything existing drugs target, so it gives us a new opportunity to fill that gap.” Previously tested drug could speed up treatment Discovering a new biological target is often just the beginning of a long drug development process. Researchers often need years of additional work to identify a suitable compound and determine whether it can be used safely in people. In this case, however, scientists may already have a promising candidate. A drug designed to inhibit CTSA had previously been developed as a potential treatment for heart failure. Although the program was eventually suspended for strategic reasons, the experimental drug had already progressed through a Phase 1 clinical trial, where its safety in humans was successfully evaluated. That prior work could provide a significant advantage. Rather than starting drug development from scratch, researchers believe the existing CTSA inhibitor may be ready to advance to a Phase 2 clinical trial to investigate its effectiveness against high cholesterol. The findings are still at an early stage and the drug has not yet been shown to lower cholesterol in humans. However, its previous clinical tests could shorten the path to determining whether this new treatment strategy works in patients. “Fortunately, there is an experimental drug on the shelves that has already been shown to be safe in humans,” Saltiel said. “We hope to test whether this could be effective by conducting a clinical trial, which could potentially bring a new treatment option to patients much sooner than expected.” Co-authors of the study include Xue Feng, Shuo Zhang, Yuqi Wang, Twisha Kurlagunda, Allyssa Sit, Sadatsugu Sakane, Se Yong Park, Churaibhon Wisessaowapak, Kaylee Nguyen, Jamie Yan, Himani Pothulu, Catherine Dinh, Felicia Chu, Yuyao Ren, Bichen Zhang, Patrick Secrest, Chao-Wei Hung, Preethi Veeragandham, Yuliya Skorobogatko, Tatiana Kisseleva and Amit R. Majithia of UC San Diego; Priya Jaishankar, Pusu Yang and Adam Renslo of the University of California, San Francisco; Linmeng Han and Peng Zhao of the University of Texas Health Science Center at San Antonio; and Philip LSM Gordts of the University of Utah. The research was partially funded by the National Institutes of Health (grants P30DK063491, R01DK117551, R01DK128796, and R01DK135289) and a postdoctoral fellowship from the American Diabetes Association (1-25-PDF-76).
