Recognizing National Cholesterol Awareness Month
While many BPS members work on very basic biological principals and subjects, the work does relate to our understanding of disease and contribute to cures and treatments down the road. In recognition that September is National Cholesterol Awareness Month, we asked Daniel Ory, the senior author of a recent study published in Biophysical Journal, to share some information about his research related to cholesterol.
Why is it important to study cholesterol?
Cholesterol is essential for mammalian cell function by contributing to membrane bilayer structure and function. On the other hand, excess free cholesterol is toxic to the cell, and contributes to diseases, such as atherosclerosis, which are responsible for much of cardiovascular disease morbidity and mortality. Understanding the cellular mechanisms responsible for regulating cholesterol balance – or homeostasis – have led to important advances in drug development (e.g., statins) that have reduced cardiovascular mortality. Nonetheless, the current drugs are not tolerated by all that would benefit from therapy, so new drug targets are needed.
What aspect of cholesterol biology did your paper examine?
Diverse pathways have evolved to maintain cholesterol levels within a narrow range. While there has been much focus on the transcriptional pathways that govern cellular cholesterol synthesis and uptake and elimination, less well appreciated are the non-genomic mechanisms that are central to cholesterol homeostasis and operate on a much more rapid time-scale. Our study focused on the biophysical basis of the rapid cholesterol regulatory mechanisms.
What were the key findings of your study?
In response to cholesterol loading or depletion, previous studies have shown that there is a rapid equilibration between cellular cholesterol pools. In our study, to gain insight into the mechanisms underlying these responses, we performed computer simulations and used experimental systems to examine the behavior of cholesterol in membrane bilayers. We found that the position of cholesterol in membranes determines its accessibility, and that accessibility is driven not by saturation of membrane-cholesterol interactions – as previously proposed – but by bulk membrane remodeling. We believe this work supports a revised model for the mechanism of rapid cholesterol regulation.
How do these findings relate to circulating lipoprotein cholesterol?
An important aspect of in vivo cholesterol metabolism is the removal of cholesterol from peripheral organs for disposal and excretion by the liver. The biophysical mechanisms that we explore in our study are the same mechanisms responsible for transfer of cholesterol from cells, such as macrophages, to nascent high-density lipoproteins (HDL). Once lapidated with cholesterol, these lipoproteins travel to the liver for uptake and metabolism into bile acids. Through improved understanding the molecular basis of cholesterol presentation to lipoproteins, we may be able to manipulate the membrane environment to enhance cholesterol removal from cells.