Study elucidated how apoA-I mitigates the function of HDL.

University of Cincinnati (UC) researchers have determined the structure of human HDL cholesterol. They say their understanding of how the apoA-I structure modulates HDL function and its interactions with other apolipoproteins could provide insights into HDL’s ability to protect against cardiovascular diseases.

The study was led by W. Sean Davidson, Ph.D., professor in UC’s pathology and laboratory medicine department. It appears online March 13 in Nature Structural & Molecular Biology. The paper is titled “Apolipoprotein A-I structural organization in high-density lipoproteins isolated from human plasma.”

Studies of synthetically derived HDL have shown that an abundant protein in HDL, apolipoprotein A-I, plays a key role in HDL’s cardioprotective anti-inflammatory and anti-oxidative properties. Rong Huang, Ph.D., a post-doctoral fellow in Dr. Davidson’s laboratory, isolated human HDL and analyzed its 3-D structure as it circulates in human plasma.

“Previous studies have only focused on synthetic HDL made in the test tube,” Dr. Davidson points out. “By isolating human HDL, we were able to focus on the broad range of HDL particles actually circulating in humans.”

The researchers found that proteins of HDL form a cage-like structure that encapsulates its fatty cargo.  They determined that most of the HDL particles circulating in human plasma are remarkably similar in structure, but they found evidence that the particles have a twisting or shock absorber-like motion that allows them to adapt to changes in particle fat content.

Dr. Davidson and his team concluded that the majority of physiological interactions occurring with HDL, including its twisting movements, occur at the particle surface, which is dominated by the cardioprotective protein apolipoprotein A-I.

This monopolization of the particle surface, Dr. Davidson says, suggests that other proteins have very little room to bind to HDL and probably have to interact with the protein itself. This could explain how apolipoprotein A-I plays such a dominant role in HDL function and its protective effects.

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