Elevated plasma concentrations of LDL cholesterol lead to increased risk of cardiovascular disease and elevated plasma concentrations of HDL cholesterol represent a negative risk factor for cardiovascular disease. But why? Isn’t cholesterol just cholesterol?
Our lipoproteins vary in size, structure, and function. Chylomicrons, the largest, are so big that they scatter visible light and float at the density of plasma. In contrast, high density lipoproteins are quite small (< 9 nm), smaller than the molecular radius of pentameric IgM (about 12 nm). The larger, apolipoprotein B-containing particles have proportionally more triglyceride than the non-apoB particles, which are mostly protein (i.e. HDL particles are >50% protein by weight).
As for their function, things are a little less clear. In general, the triglyceride-rich particles deliver triglycerides from the liver to the periphery and in general HDL brings excess cholesterol back to the liver for disposal. All particles appear to play at least some role in delivering cholesterol to cells for maintenance of phospholipid bilayer fluidity and steroidogenesis.
Little balls of fat couldn’t possibly know where to go or how to act by themselves, so we have to consider that the protein part of the lipoproteins must be important. The proteins presumably facilitate handshakes between particles and cells and explain the intrinsic enzymatic activities of lipoproteins.
Enter lipoproteomics. Defined as the study of the proteins carried by lipoproteins, this word more practically refers to the application of state-of-the art mass spectrometric methods of protein identification to the study of lipoproteins. Before soft ionization-mass spectrometric methods became prominent, many experiments had already identified the proteins most important in lipid metabolism, including phospholipid transfer protein, lecithin:cholesterol acyltransferase, and cholesteryl-ester transfer protein. Proteomics methods have more recently been used to uncover an amazing number of proteins in various lipoproteins that may help explain many of the complex interactions between lipid metabolism and inflammation. For example, complement regulatory proteins and protease inhibitors in HDL could have very important implications for protection from acute coronary syndrome.(1) Further, concentrations in HDL of the complement regulatory protein clusterin are lower in obese and insulin resistant people,(2) which appear to be responsive to lipid-modifying therapy.(3) Also, the presence of lysozyme in apoB-containing particles(4) supplements what has been learned from mouse models of infection.(5)
Lipoproteomics experiments that have aimed to discover fundamental pathophysiological mechanisms have been plagued with one fundamental problem, which is that no one really knows how to define the different lipoprotein particles. For example, HDL particles can be purified with density gradient ultracentrifugation, size exclusion chromatography, or immunoaffinity purification of apoA-I particles, but each of these approaches generates very different particles. Different lipoproteins can also be thought of simply as different fractions of plasma, which have many proteins in common (e.g. apoE is found in all lipoprotein fractions). So, it is difficult to say that a protein found in one particle type explains the biology of that particle, without somehow implying that it isn’t active in another particle type. It will be interesting to see how these issues are sorted out.
Ideally, proteins in specific fractions will one day be used as markers of disease risk to identify people with abnormalities in lipid metabolism. These biomarkers might indicate increased systemic inflammatory responses or a higher atherosclerotic burden, or maybe even identify people with very unstable atherosclerotic plaques.