Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond

Abstract

Working at the Pasteur Institute in Paris in 1929, Michel Macheboeuf reported the fi rst detailed isolation of a lipidrich " ␣ -globulin" from horse serum, a fraction that would later become known as high density lipoprotein (HDL) ( 1 ).Although relatively rapid progress was made at characterizing the lipid composition of this fraction -phospholipids (PL, ‫ف‬ 25%), cholesterol ( ‫ف‬ 4%), triglycerides (TG, ‫ف‬ 3%) and cholesteryl esters (CE, ‫ف‬ 12%) -it took nearly 40 years to begin to sort out the complexities of the protein component.Part of the delay may have resulted from the widespread believe that "apo-HDL" was likely single protein entity, much like low-density lipoprotein (LDL), which was dominated by a single polypeptide later identifi ed as apolipoprotein (apo)B.Using amino acid analyses, early electrophoresis methods, and a variety chromatographic techniques, the fi rst HDL protein moiety was identifi ed in the late 1960s.Variously referred to as ␣ -protein, "R-Thr" peptide ( 2 ), fraction III ( 3 ), and fraction II peptide ( 4 ), it later became known as apoA-I ( 5 ).Working in parallel, these laboratories also fi rst recognized the possibility for heterogeneity within the HDL protein complement.This led to the identifi cation of a second protein later known as apoA-II ( 5 ).The signifi cance of this observation was not lost on these early pioneers.For example, the Shores Abstract Recent applications of mass spectrometry technology have dramatically increased our understanding of the proteomic diversity of high density lipoproteins (HDL).Depending on the method of HDL isolation, upwards of 85 proteins have been identifi ed, and the list continues to grow.In addition to proteins consistent with traditionally accepted roles in lipid transport, HDL carries surprising constituents, such as members of the complement pathway, protease inhibitors involved in hemostasis, acute-phase response proteins, immune function mediators, and even metal-binding proteins.This compositional diversity fi ts well with hundreds of studies demonstrating a wide functional pleiotrophy , including roles in lipid transport, oxidation, infl ammation, hemostasis, and immunity.This review summarizes the progression of our understanding of HDL proteomic complexity and points out key experimental observations that reinforce the functional diversity of HDL.The possibility of specifi c HDL subspecies with distinct functions, the evidence supporting this concept, and some of the best examples of experimentally defi ned HDL subspecies are also discussed.Finally, key challenges facing the fi eld are highlighted, particularly the need to identify and defi ne the function of HDL subspecies to better inform attempts to pharmacologically manipulate HDL for the benefi t of cardiovascular disease and possibly other maladies.-Shah, A. S., L.