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April, 2007
Mopping up Cholesterol, Nature's Way

Hoping to take a page from nature's playbook, a multi-institutional team of researchers led by Berkeley Lab biochemist John Bielicki has learned how a particle that sweeps cholesterol from the body forms in the arteries. Their goal is to create a therapy that jumpstarts this process in people who suffer from atherosclerosis, a life-threatening disease in which the blood vessels that feed the heart become clogged.

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John Bielicki's research may lead to improved ways of fighting atherosclerosis. (Photo Roy Kaltschmidt, CSO)

"We want to devise a therapeutic that mimics how nature keeps the arteries clear of cholesterol," says Bielicki, a staff scientist in the Lab's Life Sciences Division.

They're not there yet. A successful drug is still years away. But Bielicki's team has completed the necessary groundwork. In a pair of recently published studies, they reveal in unprecedented detail how the cholesterol-scouring particle, the so-called good cholesterol also known as high-density lipoprotein (HDL), is assembled.

At the heart of this process are two proteins present in the blood called apolipoprotein E and A-I. These proteins bind with another protein, called ABCA1, which resides in the membranes of certain cells that line arterial walls. When these proteins bind, ABCA1 kicks into gear and pumps cholesterol from the cell, unloading the potentially harmful substance onto the E and A-I proteins. The resulting protein-cholesterol molecule shapes itself into an HDL particle, which is then whisked away to the liver for disposal. Along the way, the HDL particle mops up still more cholesterol from the arteries. Problem solved.

Unfortunately, this bit of arterial housekeeping is short-circuited in people with atherosclerosis. Their HDL level remains low and can't keep pace with ever-thickening deposits of the fatty plaque.

To fight this problem, Bielicki's team zeroed in on the initial step that sets the HDL-assembly process in motion. Specifically, they determined how the apolipoprotein E and A-I proteins attach themselves to ABCA1.

"This is the rate-limiting step, and generally the slowest one, but when it gets started, the process takes off and everything else falls into place," says Bielicki. "Now, our research shows how this step works. We have isolated the active binding domains on apolipoprotein E and A-I that interact with ABCA1."

With this information, they can pinpoint the amino acids involved in the interaction, as well as the molecular forces that allow the proteins to extract cholesterol from arterial walls and form HDL. Their work opens the door for the development of a synthetic molecule that mimics this process — unleashing a powerful snowball effect that cleans dangerously congested arteries.

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Smaller than less dense forms of cholesterol, high-density lipoprotein (HDL) particles like the one depicted here nevertheless incorporate large proteins that are difficult to mimic artificially. To treat atherosclerosis, Bielicki and his colleagues propose a much smaller protein that can perform key initial steps in the formation of HDL.

Copying nature to fight cholesterol deposition isn't a new strategy. An artificial HDL variant under development by Pfizer Inc. has been found to reduce atherosclerosis in people. But this approach has drawbacks. It requires a large protein composed of hundreds of amino acids that is expensive and time-consuming to synthesize. In addition, because it is a variant protein and large in size, it could trigger an immunological response. And HDL has many roles besides ridding the arteries of cholesterol. This means that a synthetic HDL particle designed to mop up cholesterol will likely get sidetracked by other reactions, limiting its potency.

Instead, Bielicki proposes a much smaller protein, composed of only a few amino acids, that selectively targets the initial steps of HDL assembly. It would not become entangled in the many other roles required of HDL, which would maximize its specificity and potency. And because the synthetic protein is small, it would be cheap to manufacture and affordable to use — a critical characteristic of a drug designed to treat one of the leading causes of illness and death in the U.S. Its small size would also enable it to go unnoticed by the body's immune system, enabling it to work longer than a larger drug.

"It would be a targeted therapeutic that facilitates cholesterol transport out of the arteries," says Bielicki. "The plan is to figure out how nature works and then devise a therapeutic." This research has resulted in several Berkeley Lab patents that have been licensed.

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