Abstract
HDLs are a family of heterogeneous particles that vary in size, composition, and function. The structure of most HDLs is maintained by two scaffold proteins, apoA-I and apoA-II, but up to 95 other "accessory" proteins have been found associated with the particles. Recent evidence suggests that these accessory proteins are distributed across various subspecies and drive specific biological functions. Unfortunately, our understanding of the molecular composition of such subspecies is limited. To begin to address this issue, we separated human plasma and HDL isolated by ultracentrifugation (UC-HDL) into particles with apoA-I and no apoA-II (LpA-I) and those with both apoA-I and apoA-II (LpA-I/A-II). MS studies revealed distinct differences between the subfractions. LpA-I exhibited significantly more protein diversity than LpA-I/A-II when isolated directly from plasma. However, this difference was lost in UC-HDL. Most LpA-I/A-II accessory proteins were associated with lipid transport pathways, whereas those in LpA-I were associated with inflammatory response, hemostasis, immune response, metal ion binding, and protease inhibition. We found that the presence of apoA-II enhanced ABCA1-mediated efflux compared with LpA-I particles. This effect was independent of the accessory protein signature suggesting that apoA-II induces a structural change in apoA-I in HDLs.
Highlights
HDLs are a family of heterogeneous particles that vary in size, composition, and function
We found that the presence of apoA-II can have profound effects on the proteomic content of the isolated particles and on their function in terms of cholesterol efflux
lipoproteins with apoA-I and no apoA-II (LpA-I) and LpA-I/A-II particles were isolated by applying plasma directly to the anti-apoA-I column followed by the anti-apoA-II column
Summary
HDLs are a family of heterogeneous particles that vary in size, composition, and function. LpA-I exhibited significantly more protein diversity than LpA-I/A-II when isolated directly from plasma We found that the presence of apoA-II enhanced ABCA1-mediated efflux compared with LpA-I particles This effect was independent of the accessory protein signature suggesting that apoA-II induces a structural change in apoA-I in HDLs.—Melchior, J. The term HDL refers to a family of diverse subspecies that share similar hydrated densities These can vary widely in size, protein/lipid composition, and charge [reviewed in [1]]. Recent MS studies across different laboratories have found up to 95 different proteins in HDL preparations [2] This compositional heterogeneity mirrors a well-known functional heterogeneity [3] in that HDLs can attenuate the oxidation of LDLs [4], reduce vascular cell-mediated inflammation [5], regulate proteolytic and thrombotic pathways [reviewed in [6]], reduce cellular apoptosis [7], and affect insulin secretion from pancreatic cells [8].
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