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Liver Enzyme May Be at Root of Heart Disease

Researcher hopes to test the theory next in monkeys

SATURDAY, April 30, 2005 (HealthDay News) -- A single enzyme produced by the liver may be guilty of cholesterol accumulation, hardening of the arteries, and death by heart attack.

So charges one researcher, who has set out to be the judge, jury and scientific executioner of ACAT2 -- a poorly understood enzyme that appears to play a major role in promoting atherosclerosis.

According to researcher Lawrence Rudel, ACAT2 actively tweaks the structure of both dietary and liver-produced cholesterol, enabling it to move about the bloodstream much more easily. The molecularly altered cholesterol then takes up residence in blood vessel walls, clogging arteries and leading to cardiovascular disease.

Rudel backed up his thesis with incriminating animal research evidence. As a pathology and biochemistry professor at Wake Forest University School of Medicine, he has most recently focused on the workings of ACAT2 among mice.

Rudel presented his research this week at the ongoing American Heart Association conference in Washington, D.C.

He reported that in one set of studies, mice that were genetically engineered to not produce any ACAT2 had 85 percent less hardening of the arteries than mice that produced normal amounts of ACAT2.

Rudel followed this up by inserting a molecular compound specifically designed to inhibit ACAT2 production in a group of normal mice.

The compound had been developed by the cardiovascular division of Isis Pharmaceuticals, based in Carlesbad, Calif. Rudel said the drug development company donated the compound free of charge, with no strings attached.

After ceasing ACAT2 production, the compound-exposed mice were found to have 70 percent less hardening of the arteries than the mice that were not exposed.

"I know this must sound crazy to people, but that's in fact what happens," said Rudel. "It looks like the enzyme really does what we think it does, and when we inhibit the enzyme, it prevents the disease process."

Rudel pointed out that while ACAT2 is actually found in both the liver and the intestine, the compound studies with mice targeted only liver production of the enzyme.

"So that makes the results even more remarkable," he added, "in that we only had to inhibit the enzyme in one tissue -- the liver -- to inhibit the hardening of the walls."

Rudel suggested that physicians may one day routinely screen for ACAT2 levels in patients, in addition to assessing cholesterol levels.

Cholesterol is manufactured naturally by the liver, but is also present in a range of foods such as meats, fish and dairy products. Experts have warned for decades that a build-up of cholesterol can increase the risk for cardiac illness.

Rudel has moved on to pilot research involving monkeys, hoping to replicate the success of his mouse studies.

He said it will take approximately two to three years to fully test the effect of the same compound on the primates, after which -- if all goes well -- he will move on to human trials.

"There's a good science base for this research, and the closer we get to the human system, the more exciting it will be in terms of the potential for this to be developed into a drug," said Dr. Edward A. Fisher, a professor of cardiovascular medicine at New York University and director of the NYU Lipid Treatment and Research Center.

While confirming that Rudel and Wake Forest University have been at the forefront of this type of research using non-human primates, Fisher emphasized the critical nature of the stage Rudel is entering.

"The history of things that work in mice and rats and then work in humans is checkered," he cautioned. "But the batting average for things that work in monkeys and things that work in humans is very high. Rudel has been a major investigator. And he has worked out experimental protocols for at least 20 years, so he'll be able to know relatively rapidly if this works in monkeys."

"So it's promising, to this degree," added Fisher. "And I think there's no question that if he gets good results in monkeys, then this will be developed as a drug for humans."

More information

For more on the connection between cholesterol, diet and cancer, check out the American Cancer Society .

SOURCES: Lawrence Rudel, Ph.D., professor, departments of pathology and biochemistry, Wake Forest University School of Medicine, Winston-Salem, N.C.; Edward A. Fisher, M.D., Ph.D., professor, cardiovascular medicine, New York University, and director, NYU Lipid Treatment and Research Center, both in New York City; April 28, 2005, presentation, American Heart Association, annual conference on arteriosclerosis, thrombosis and vascular biology, Washington, D.C.
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