Your Density Isn't Your Destiny

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Photo by Roy Kaltschmidt

Gang Ren (standing) and Lei Zhang at Berkeley Lab's Molecular Foundry were part of a team that found new evidence to explain how cholesterol is moved from HDLs to LDLs.

Being someone's density, and destiny, can be a great thing, as George McFly discovered in the movie Back to the Future. ("I'm George, George McFly. I'm your density. I mean…your destiny.") But it can also be bad thing, if it's the sort of density that leads to the destiny of heart disease.

Fortunately, researchers at Lawrence Berkeley National Laboratory's (Berkeley Lab's) Molecular Foundry, a DOE Nanoscale Science Research Center, recently found new evidence of how good cholesterol goes bad, which could improve the destiny of the estimated one in six Americans suffering from high blood cholesterol.

Specifically, in research supported in part by the Office of Science, scientists looked at how cholesterol is transferred between different carriers. For all its bad press, people actually need cholesterol—cells use it in a variety of ways including digestion (via the manufacture of bile acids), the production of Vitamin D and various hormones and even the stabilization of their membranes.

The body moves cholesterol around via carriers called lipoproteins, which are sort of like barrels, with proteins on the outside and cholesterol stuffed within. Low density lipoproteins (LDLs) are thought of as "bad" cholesterol, since they can build up in arteries, the rivers through which blood flows, eventually obstructing and even damming them, leading to heart disease. In contrast, high density lipoproteins (HDLs) are called "good" cholesterol because they help carry cholesterol away from artery walls, and to the liver for ultimate disposal.

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Image courtesy of Berkeley Lab.

(1) CETP penetrates HDL to its cholesterol core. (2) Upon interaction with LDL/VLDL, molecular forces cause the formation of pores at either end of CETP. (3) These pores connect with CETP’s central cavities to form a tunnel for the transfer of cholesterol to LDL/VLDL, which (4) reduces HDL in size.

Before the recent work at Berkeley Lab, scientists knew that cholesterol can be moved from HDLs to LDLs via a protein called cholesteryl ester transfer protein (CETP). They also knew that blocking the protein leads to more HDLs and fewer LDLs, lowering the risk of heart disease—there are even a few CETP inhibitors now in clinical trials. However, they didn't know exactly how the protein does its job.

That's where researchers at the Foundry stepped up. Using the advanced nanoscale imaging tools and techniques uniquely available at Office of Science facilities, they constructed the first structural images of the protein interacting with HDLs and LDLs, as well as a detailed analysis of how CETP actually works. They found that CETP acts as a sort of tunnel, or tap, which first plugs into the HDL, and then into the LDL. When the connection is made between the two "barrels," the protein pipe opens, and cholesterol is able to flow from the HDL into the LDL.

By providing new insight into the specific structure of CETP and the precise mechanism by which it works, scientists at the Foundry are presenting new potential targets for future medicines. That's the hope, that it's a breakthrough that'll lead to real benefits. And one day, with a little luck, and likely a whole lot more help from the Office of Science, those suffering from high cholesterol may cheerfully discover that their density is not their destiny.

The Department's Office of Science is the single largest supporter of basic research in the physical sciences in the United States, and is working to address some of the most pressing challenges of our time. For more information about Berkeley Lab and the Foundry, please go to: http://www.lbl.gov/ and http://foundry.lbl.gov/.

Charles Rousseaux is a Senior Writer in the Office of Science.