Researchers at UT Southwestern Medical Center have identified a protein that acts as a key regulator of how the liver releases cholesterol carrying particles into the bloodstream. The discovery could eventually lead to new treatments for heart disease and fatty liver disease.
The study, published in the American Heart Association journal Circulation, focused on a protein called HELZ2. Scientists found that HELZ2 helps control the activity of apolipoprotein B (APOB), a gene required to produce apoB proteins that form lipoproteins, the particles responsible for transporting cholesterol and fats through the body.
“These particles are a major driver of plaque buildup in the arteries,” said senior author Zhao Zhang, Ph.D., Assistant Professor in UT Southwestern’s Center for the Genetics of Host Defense and of Internal Medicine. “What we found is that HELZ2 acts as a powerful control point for how many cholesterol-carrying particles ultimately enter the bloodstream.”
How HELZ2 Reduces Harmful Cholesterol
The team discovered that HELZ2 works by shortening the lifespan of APOB messenger RNA (mRNA) inside liver cells. Messenger RNA carries the instructions needed for cells to make proteins. When HELZ2 activity rises, the APOB message breaks down more quickly, resulting in lower production of apoB proteins and fewer cholesterol carrying lipoproteins entering the blood.
“Most previous research focused on what happens to apoB after it’s already made,” said Yiao Jiang, Ph.D., a postdoctoral researcher in the Zhang Lab 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.”
To uncover HELZ2’s role, the researchers used a large scale genetic screening system developed by Nobel Prize winner Bruce Beutler, M.D., Director of the Center for the Genetics of Host Defense and Professor of Immunology and Internal Medicine at UT Southwestern. While studying unusual fat buildup in the livers of mice, the scientists identified a gain-of-function mutation that increased HELZ2 activity and reduced the stability of APOB mRNA in the liver.
Lower Blood Cholesterol but More Liver Fat
Mice carrying the HELZ2 mutation produced fewer lipoproteins, including LDL (low-density lipoprotein) cholesterol and triglycerides, in their bloodstream. The animals also showed greater protection against atherosclerosis, the artery clogging disease linked to heart attacks and strokes.
At the same time, however, more fat accumulated in their livers. Mice without the mutation showed the opposite effect, highlighting a delicate balance between cholesterol circulating in the blood and fat stored in the liver.
“We can think of HELZ2 as a kind of dial between the liver and the bloodstream,” Dr. Zhang said. “Turning it up lowers cholesterol in the blood but increases liver fat. Turning it down does the reverse. That balance makes HELZ2 especially interesting as a potential therapeutic target.”
A Potential Alternative to Statins
Statins remain the most widely prescribed drugs for lowering cholesterol and reducing heart disease risk. But researchers say the HELZ2 discovery points to a completely different way of controlling harmful cholesterol particles.
Instead of targeting cholesterol after it has already been produced, HELZ2 influences the process at the genetic instruction stage before the proteins are even made. Scientists believe carefully adjusting HELZ2 activity could eventually help reduce dangerous cholesterol levels while also offering new strategies for treating fatty liver disease.
“The idea that we can control apoB at the RNA level represents a major shift in how we think about cholesterol regulation,” Dr. Zhang said. “It gives us a new molecular lever — and potentially a new set of tools — for tackling these conditions.”
Dr. Beutler, a Regental Professor, shared the 2011 Nobel Prize in Physiology or Medicine for discovering an important family of receptors found on immune cells. He holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr. Dr. Beutler is also a member of the Harold C. Simmons Comprehensive Cancer Center.
The research was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (R00DK115766 and R01DK130959).