Assistant Professor, Oregon Health & Science University
On the cholesterol front, we want to know: Is good HDL really good? If so, why? Or have we found a way through our lifestyle to make it bad so it’s no longer working? We do know that HDL levels have a hereditary component; roughly 50% is unchangeable. So you can only modify the remaining 50%. You can think of HDL particles as tiny balls, about one thousandth the size of a cell nucleus, infiltrating every tissue in the body, removing cholesterol from cells and bringing it back to the liver. That’s their job. Historically we always cared about the number of “balls” but that’s now considered irrelevant because so many studies have shown that raising HDL levels does not necessarily provide cardiovascular benefits.
The discussion now is around how efficient, how good these particles are at removing cholesterol from cells and bringing it back to the liver. Testing for function isn’t at the clinical level yet but there are four large epidemiology studies looking at HDL function and cardiovascular risk. What I want to know is the function genetically regulated? If so, what’s the wiggle room for improvement? I currently have an American Heart Association Scientist Development Grant to look at HDL proteome (a set of proteins expressed) and function across hundreds of strains of mice. I’m using a genetic tool developed by UCLA that allows you to map a phenotypic trait, say HDL function, and then identify a couple of genes that associate with that trait – so, these genes regulate that trait. In my studies I’ve shown that HDL function and HDL proteome are genetically regulated. The most amazing part is that just by looking at the HDL proteome of 80 to 100 proteins, you can predict the genealogy of a trait with statistical analysis.
Another interesting area I’m exploring is we know HDL function correlates with CVD but in most cases, it’s not the CVD that kills you, it’s a stroke event. But why? The relationship between HDL cholesterol and stroke is not very well defined. So I’m working with Nabil Alkayed, M.D., Ph.D., director of the Division of Cerebrovascular Research in the OHSU School of Medicine to better understand this link. We tested 15 patients and found a tremendous difference not only in HDL function but also in the HDL proteome. The reason that’s important is we believe protein dictates function. If we understand what these HDL “balls” are made of protein-wise then maybe we can understand why they’re good at, or failing, at their function. Sergio Fazio M.D., Ph.D., head of preventive cardiology introduced me to REGARDS (Reasons for Geographic and Racial Differences in Stroke) researchers and I’ve been granted access to samples from this large epidemiology study to further explore this research question. I have 3,000 samples total – 1,000 healthy, 1,000 CVD, and 1,000 stroke to look at HDL biology, function, proteome, and genetics. Now I need to do the science and have requested funding from NIH.