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Turning Potential Into Reality
CHORI Scientists Use ApoA-V to Reduce Triglycerides

In an exciting new study published in Arteriosclerosis, Thrombosis and Vascular Biology, CHORI scientists Trudy M. Forte, PhD, Robert O. Ryan, PhD, Xiao Shu, PhD and their colleagues have demonstrated the potential of using apoliprotein A-V (apoA-V) as a novel therapeutic tool to reduce triglycerides. People are much more familiar with cholesterol, and the risks associated with elevated cholesterol, but elevated triglyceride (TG) in the blood is also independently associated with increased risk of heart disease – the number one cause of death in the United States.

"It's a significant problem, but many people are not as clued into TG as they are to cholesterol, even though it causes increased risk for type 2 diabetes, obesity, insulin resistance and coronary disease," says Dr. Forte.



It is well known that TG in the bloodstream is broken down through lipolysis – in which the lipoprotein lipase hydrolyzes the TG and releases fatty acid. The fatty acids are used as energy, with the excess stored in fat cells. About 10 years ago, however, researchers discovered an unknown protein that has been shown to be significantly associated with TG levels: apoA-V.

"Plasma lipids have proteins on their surfaces that help direct the fate of the lipids. Some of these proteins are found in relatively high concentrations in the blood. ApoA-V, however, made by the liver, is present in the blood in extremely low concentrations," explains Dr. Forte.
“This makes apoA-V a bit of an enigma, because even though it is present in very low quantities it is essential to maintaining normal TG levels.”
"This makes apoA-V a bit of an enigma, because even though it is present in very low quantities it is essential to maintaining normal TG levels."

So essential in fact, that knockout mice genetically engineered to lack apoA-V have extremely high TG levels, while transgenic mice genetically engineered to over-express apoA-V have very low TG.

"So here you have a protein in very small quantities that has a very large effect on TG metabolism. We are still trying to understand that," says Dr. Forte.
Enter the latest groundbreaking study, in which Dr. Forte and her colleagues wanted to find out what would happen if apoA-V was injected into apoA-V knockout mice.

"We wanted to know if we could lower TG in mice lacking apoA-V by simply reintroducing apoA-V into the bloodstream, because if so, it could be a very worthwhile avenue for trying to reduce TG in human beings," Dr. Forte explains.

Scientists can't just inject apoA-V directly into the bloodstream however, because it is a hydrophobic protein that is insoluble in water. To make the protein soluble and easy to inject into the bloodstream, Dr. Forte and her colleagues combined the apoA-V with phospholipid to produce an apoA-V reconstituted high density lipoprotein (rHDL) which allows it to be injected directly into the bloodstream.

"What we found was that apoA-V-rHDL injection lowered TG 85 percent over an eight hour period," says Dr. Forte. "That was kind of exciting, so we did a few other things to figure out what is required for this event to happen."
The results of the additional testing elucidated two key players required for effective lipolysis – and thus clearing of TG: the heparin-binding region of apoA-V and a protein called glycosylphosphatidylinositol-anchored HDL-binding protein 1, or GPIHBP1. Recent studies in mice have shown that without GPIHBP1, lipolysis is severely reduced and TG levels extremely elevated.

"When we injected apoA-V into genetically engineered mice without GPIHBP1, we had the exact opposite response compared to the apoA-V knockout mice – nothing at all happened. The highly elevated levels of TG were not reduced," says Dr. Forte.

"When you combine these results – that in apoA-V knockout mice we achieved an 85 percent reduction in TG, but in the GPIHBP1 knockout mice we achieved no reduction at all - this really suggests that there is a partnership between lipase, which triggers lipolysis, GPIHBP1 and apoA-V, and that you need all three in order to obtain the optimum lipolysis required to reduce TG levels."
“This study suggests that there is a partnership between lipase, which triggers lipolysis, GPIHBP1 and apoA-V, and that you need all three in order to obtain the optimum lipolysis required to reduce TG levels.”
Although further studies are required to fully elucidate the mechanisms of this partnership, the new study provides evidence that apoA-V may just hold the key to reducing triglycerides in some clinical settings.

"What we have here is the potential for apoA-V to have some therapeutic benefit to human beings in terms of reducing TG levels and helping prevent heart disease," says Dr. Forte. " To move that potential another step closer to reality, we need to confirm similar results in other mouse models with elevated TG."

Dr. Forte and her colleagues hope to confirm the results in continued studies throughout the next year.

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Tuesday, May 17, 2011 8:19 AM

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