Breakthrough in Understanding Cholesterol Protein

In a new study, University of Missouri researchers have unraveled the structure of ApoB100, a crucial protein associated with “bad” cholesterol, potentially transforming heart disease treatments.

For decades, low-density lipoproteins (LDL) — the notorious “bad” cholesterol — have been flagged as a major culprit in heart disease. However, the intricate workings of these microscopic adversaries have remained largely elusive. Now, in a new study published in Nature, University of Missouri researchers have, for the first time, decoded the shape and structure of ApoB100, a critical protein that envelopes LDL particles, allowing their passage through the bloodstream.

This revelation holds promising potential for the development of new drugs aimed at targeting LDL, offering more precise treatments for high cholesterol and heart disease, and potentially mitigating the side effects of commonly used medications like statins.

Advanced Technique

Researchers Zachary Berndsen and Keith Cassidy were key in this discovery, owing to their expertise in cryo-electron microscopy. This advanced technique, which uses electrons to map out the 3D structure of biological molecules, was instrumental in their breakthrough.

“These cryo-electron microscopes allow us to see things at a much higher resolution than the traditional microscopes familiar to most of us,” Berndsen, an assistant professor in the MU School of Medicine, said in a news release. “Instead of just seeing a cell’s shape, for instance, these tools allow us to now see what individual proteins are shaped like, which are thousands of times smaller than a typical cell, and that is how we made our recent discovery. What this technology means for scientific advancement is incredible, and we are thankful Mizzou invested in both us and our research.”

Berndsen’s use of the nearly two-story-tall cryo-electron microscope provided insights into the ApoB100 structure.

Cassidy, leveraging artificial intelligence and MU’s high-powered supercomputers known as Hellbender, further detailed the protein’s intricacies.

“We often think of cholesterol as purely bad, but in general it is actually a very useful and beneficial molecule involved in numerous important processes throughout the body, such as building hormones and maintaining cell membrane fluidity,” Cassidy, an assistant professor of biological physics in the College of Arts and Science, said in the news release.

“By integrating an AI neural network called AlphaFold with the cryo-electron microscopy images, we were able to get an even more detailed and higher-resolution picture of the structure of ApoB100. Ideally, this can lead to more targeted treatments that reduce heart disease-related risks without interfering with all the benefits cholesterol brings throughout the body,” he continued.

The Impact

This discovery not only enhances our understanding of fat and cholesterol metabolism but also paves the way for more specific testing and treatment for “bad” cholesterol.

“The most common ways of testing for cholesterol levels are currently not very specific,” Berndsen added. “Going forward, if we can test for how many copies of this ApoB100 are in your blood, that would be a more accurate indicator of risk for heart disease.”

The research holds personal significance for both Berndsen and Cassidy, who have family histories of heart disease, the leading cause of death globally.

“We are trying to bridge the gap between the basic science we are doing now and the applied health benefits down the road,” Berndsen added. “Our work can help benefit the health of the general public, so it is very rewarding to do what we do.”

The study marks a significant milestone, shedding light on a protein fundamental to cholesterol regulation and heart health.