Scientists at UT Southwestern Medical Center have uncovered a protein that acts as a molecular gatekeeper, controlling how the liver releases cholesterol-carrying particles into the bloodstream. The finding could reshape how doctors treat heart disease and fatty liver conditions, offering an entirely different approach from the statins that have dominated cholesterol management for decades.
The research, published in the American Heart Association journal Circulation, centers on a protein called HELZ2. Researchers discovered that this protein regulates apolipoprotein B, a gene essential for producing the particles that ferry cholesterol and fats through the body. These particles are the primary culprits behind arterial plaque buildup that leads to heart attacks and strokes.
"What we found is that HELZ2 acts as a powerful control point for how many cholesterol-carrying particles ultimately enter the bloodstream," said Zhao Zhang, Ph.D., an assistant professor in UT Southwestern's Center for the Genetics of Host Defense. Zhang served as senior author on the study.
How the Switch Works
The research team discovered that HELZ2 operates by shortening the lifespan of messenger RNA that carries instructions for making apoB proteins. Think of it like turning down a dimmer switch on a genetic instruction manual. When HELZ2 activity increases, the apoB message degrades faster inside liver cells, leading to fewer proteins being produced and fewer harmful particles entering the blood.
"Most previous research focused on what happens to apoB after it's already made," explained Yiao Jiang, a postdoctoral researcher and study co-author. "What surprised us is that HELZ2 acts much earlier, by controlling how long the apoB message survives before the protein is even produced."
Scientists uncovered HELZ2's role using a genetic screening system while studying fat buildup in mouse livers. They identified a genetic mutation that increased HELZ2 activity and destabilized the instructions for making apoB.
The Trade-Off
The results revealed a delicate biological balance. Mice with the HELZ2 mutation produced fewer dangerous lipoproteins like LDL cholesterol and triglycerides in their blood. They also showed stronger protection against atherosclerosis. But the flip side emerged quickly: fat accumulated more heavily in their livers.
Mice without the mutation showed the opposite pattern, suggesting that turning up HELZ2 lowers blood cholesterol at the cost of increased liver fat storage, while turning it down does the reverse.
"We can think of HELZ2 as a kind of dial between the liver and the bloodstream," Zhang said. "That balance makes HELZ2 especially interesting as a potential therapeutic target."
A New Path Beyond Statins
Statins have been the standard treatment for high cholesterol for years, working by limiting how much cholesterol the body produces overall. The HELZ2 discovery points to a fundamentally different strategy that could eventually complement or augment existing drugs.
Rather than controlling cholesterol production after the fact, manipulating HELZ2 would intercept the process at the genetic instruction level before proteins are even made. Researchers believe fine-tuning HELZ2 activity could reduce dangerous cholesterol while simultaneously offering fresh approaches to treating fatty liver disease, a growing health concern with limited treatment options.
"The idea that we can control apoB at the RNA level represents a major shift in how we think about cholesterol regulation," Zhang said. "It gives us a new molecular lever and potentially a new set of tools for tackling these conditions."
The work was supported by the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health.
Author Jessica Williams: "This is exactly the kind of discovery that could open entirely new drug development pathways, though the trick will be figuring out how to target HELZ2 without creating unintended metabolic consequences."
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