Dallas scientist wins award from American Heart Association for genetic discovery

A Dallas scientist has been recognized by the American Heart Association for uncovering how a gene can fatten livers while also protecting arteries from dangerous plaque.

Zhao Zhang, an assistant professor at UT Southwestern Medical Center, recently won the association’s inaugural Jack Sarver Prize in Basic Science for work that could shed new light on metabolic syndrome, a group of conditions that raises the risk of heart disease, stroke and Type 2 diabetes. It affects tens of millions of Americans, according to one estimate from 2017.

The Jack Sarver Prize was created this year to honor a family who has endured generations of heart disease. It recognizes early- and midcareer scientists whose work advances cardiovascular science and helps reduce the toll of heart disease and stroke, according to the American Heart Association, which is based in Dallas. Zhang was awarded $25,000 to further his research.

The award also includes the Jack Sarver Prize in Clinical Science, given to Dr. Zainab Mahmoud of Washington University in St. Louis for her research into using low-dose aspirin among Nigerian women to help prevent preeclampsia, a dangerous pregnancy complication.

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Dr. Stacey Rosen, the American Heart Association’s volunteer president, said in a news release that Mahmoud and Zhang’s research “touches on the very foundation on which this award was established — preventing cardiovascular disease to improve the lives of people for generations to come. It truly embodies the mission of the American Heart Association to be a relentless force for a world of longer, healthier lives.”

Destroying fat’s ferry

In the United States, 1 in 3 adults has metabolic syndrome, according to the National Institutes of Health. The condition is defined by high blood pressure, high blood sugar, abdominal obesity, high blood triglycerides and low levels of HDL, the “good” cholesterol.

People who have three or more of these risk factors are considered to have metabolic syndrome, according to the NIH.

When Zhang started his lab at UT Southwestern five years ago, he set out to better understand what drives metabolic syndrome, hoping to uncover new ways to treat it and prevent the often lifelong, debilitating diseases it can cause.

Zhao Zhang is an assistant professor at UT Southwestern Medical Center.

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Like many scientists probing the hidden mechanics of human biology, he began with mice. Zhang and his colleagues chemically induced the animals to develop random genetic mutations and then watched for any signs that something in the mice’s metabolism had gone awry. When they saw those changes, they combed through the animals’ DNA to pinpoint which mutation might be responsible.

In one group of mice, Zhang traced the animals’ obesity and fatty livers to a single gene. That gene, called HELZ2, encodes an enzyme that breaks down messenger RNA, or mRNA, the molecule that carries the genetic instructions cells use to make proteins. In this case, the mutated gene made the enzyme overactive, chewing up the mRNA needed to build apolipoprotein B, a protein that ferries fat and cholesterol throughout the body.

A majority of this protein is produced by the liver, Zhang said, so when the enzyme is overactive, it causes most or all of the protein’s mRNA in that organ to be degraded and fat to accumulate. If more than five to 10% of the liver’s weight is fat, this leads to fatty liver disease, also known as steatosis. The condition does not always cause serious health problems, but some people can develop liver damage if the fat triggers inflammation.

On the flip side, because there was almost no apolipoprotein B circulating in the blood, the mice didn’t show signs of atherosclerosis, or the buildup of plaque in blood vessels. Studies have found that an excess amount of that protein appears to drive this plaque formation and, with it, the risk of heart attacks, strokes and other cardiovascular diseases.

Zhang said early data suggests a similar genetic mutation may occur in humans. But he noted more studies are needed to confirm that and to determine whether the overactive enzyme has a similar effect in people.

Looking ahead

Eventually, Zhang hopes his work could lead to new ways to treat conditions such as metabolic dysfunction–associated steatotic liver disease, or MASLD, and atherosclerosis. In MASLD, fat builds up in the liver, triggering inflammation and damage; it’s a growing but often overlooked problem among people with Type 2 diabetes, especially those with obesity.

Those treatments could include therapies that dial down the gene’s activity so fat doesn’t build up in the liver. One gene therapy now in development has shown it can lower cholesterol levels in people with familial hypercholesterolemia, an inherited condition that raises the risk of heart disease and premature death. And last year, the U.S. Food and Drug Administration approved a first-of-its-kind drug for fatty liver disease. The drug, called Rezdiffra, or resmetirom, works by telling the liver to produce less cholesterol, which in turn lowers the amount of fat in that organ.

Zhang said this gene’s double-edged effect — fattening the liver while shielding arteries from atherosclerosis — means future research will need to find drugs that strike a healthy balance. The goal, he said, is to treat fatty liver disease or artery plaque without making the other problem worse.

Miriam Fauzia is a science reporting fellow at The Dallas Morning News. Her fellowship is supported by the University of Texas at Dallas. The News makes all editorial decisions.

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