When LDL cholesterol accumulates in the blood, it leads to the development of plaques in arteries, making it more difficult for blood to circulate. Researchers at UC San Diego have discovered a new pathway through which a high cholesterol diet impacts the ability of the body to clear harmful LDL cholesterol from the bloodstream.
Image Credit: Scientific Frontline
Scientific Frontline: Extended "At a Glance" Summary: Cathepsin A Inhibition for Cholesterol Management
The Core Concept: A newly identified biological pathway explains how high-cholesterol diets degrade the liver's ability to clear low-density lipoprotein (LDL) cholesterol from the bloodstream, a process that can be reversed using an existing investigational drug.
Key Distinction/Mechanism: Unlike current treatments, such as statins or PCSK9 inhibitors that work by preserving or increasing LDL receptors, this approach targets a previously unknown degradation mechanism. High dietary cholesterol activates the Ral protein, which relies on the enzyme cathepsin A (CTSA) to deplete LDL receptors; inhibiting CTSA stabilizes these receptors and significantly lowers circulating LDL cholesterol.
Major Frameworks/Components:
- LDL Receptors: Surface proteins on liver cells that act as docking stations to extract and process LDL cholesterol from the blood.
- Ral Protein: A cellular protein activated by dietary cholesterol that initiates the reduction of available LDL receptors.
- Cathepsin A (CTSA): The specific enzyme responsible for the downstream depletion and turnover of LDL receptors.
- CTSA Inhibitor: A small molecule drug, originally developed and proven safe in Phase 1 human trials for heart failure, that successfully blocks CTSA to maintain LDL receptor levels.
Branch of Science: Molecular Biology, Biochemistry, Pharmacology, and Cardiology.
Future Application: The immediate repurposing of the shelved CTSA inhibitor for Phase 2 clinical trials, potentially accelerating the release of a novel therapeutic option for patients unable to achieve safe cholesterol levels with existing medications.
Why It Matters: Cholesterol-related cardiovascular disease remains the leading global cause of death. This discovery identifies a biological pathway completely separate from those targeted by current drugs, offering a vital alternative for patients experiencing treatment resistance or adverse side effects.
Cholesterol-related heart disease remains the leading cause of death worldwide. While doctors have more tools than ever to treat it, many patients still cannot achieve safe cholesterol levels or cannot tolerate the side effects of available medications. Now, researchers from the University of California San Diego School of Medicine have uncovered a hidden biological pathway that explains why high-cholesterol diets steadily chip away at the body's ability to clear harmful low-density lipoprotein (LDL) cholesterol from the blood, and they have identified a drug candidate already proven safe in humans that could potentially target it. The results are published in Nature.
"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, PhD, professor of medicine at the 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."
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 more LDL receptors on liver cells, the more cholesterol gets cleared from the blood—which is why most cholesterol-lowering drugs, such as statins or PCSK9 inhibitors, work by preserving or increasing the number of these receptors.
The new research, conducted in a combination of mouse and human cells, reveals a previously unknown mechanism that quietly works against the cholesterol-removal process, slowly reducing the number of LDL receptors and contributing to high blood cholesterol. The team found that this process begins when a protein called Ral—which Saltiel has 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.
This depletion process ultimately relies on an enzyme called cathepsin A (CTSA). The researchers found that blocking CTSA with a small-molecule inhibitor was enough to stabilize LDL receptors and dramatically lower circulating LDL cholesterol in mice.
"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," said Saltiel. "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."
— Alan Saltiel
After a fundamental biological breakthrough, it typically takes significant additional research to find drugs that target it. However, in this case, a CTSA inhibitor has already been through the early stages of drug development, with the initial goal of treating heart failure. While it was eventually shelved for strategic reasons, the drug had previously advanced to a phase 1 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 2 trial for high cholesterol.
"Luckily, there's an experimental drug sitting on the shelf that's already been shown to be safe in humans," said Saltiel. "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."
Funding: This study was funded in part by the National Institutes of Health (grants P30DK063491, R01DK117551, R01DK128796, and R01DK135289) and an American Diabetes Association postdoctoral fellowship (1-25-PDF-76).
Published in journal: Nature
Title: Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover
Authors: Xue Feng, Shuo Zhang, Yuqi Wang, Twisha Kurlagunda, Allyssa Sit, Priyadarshini Jaishankar, Pusu Yang, Sadatsugu Sakane, Se Yong Park, Churaibhon Wisessaowapak, Kaylee Nguyen, Jamie Yan, Himani Pothulu, Catherine Dinh, Felicia Chu, Yuyao Ren, Bichen Zhang, Patrick Secrest, Linmeng Han, Chao-Wei Hung, Preethi Veeragandham, Yuliya Skorobogatko, Tatiana Kisseleva, Philip L.S.M. Gordts, Adam R. Renslo, Peng Zhao, Amit R. Majithia, and Alan R. Saltiel
Source/Credit: University of California San Diego | Miles Martin
Edited by: Scientific Frontline
Reference Number: mbio062426_01