Lipoproteomics: using mass spectrometry-based proteomics to explore the assembly, structure, and function of lipoproteins

Abstract

Lipoproteins are centrally important in lipid transport, fuel metabolism, and cardiovascular disease. The prototypic lipoprotein has an outer shell of amphipathic lipids and proteins that solubilizes a hydrophobic lipid core. Lipoprotein-associated proteins have classically been viewed as structural elements and factors important in lipid metabolism. Recent mass spectrometric analyses reveal that the protein cargo of lipoproteins is much more diverse than previously appreciated, raising the possibility that lipoproteins play previously unsuspected roles in host defense mechanisms and inflammation. They further suggest that lipoprotein-associated proteins can identify humans at increased risk of cardiovascular disease. Here, we summarize recent developments in lipoproteomics, the proteomic analysis of lipoproteins. We also discuss the promises and challenges this powerful analytical strategy offers for expanding our understanding of the biology and structures of lipoproteins.

Fig. 1.

Overview of lipoprotein metabolism. Chylomicrons deliver triglycerides derived from the intestine into blood. Following triglyceride lipolysis to free fatty acids (FFAs) by peripheral tissues, chylomicron remnant particles are cleared by the liver via LDL receptor (LDL-R) related protein (LRP). The liver uses endogenously synthesized triglyceride and cholesterol as well as lipids derived from chylomicron remnants to synthesize VLDL. Triglyceride-rich VLDL is converted by lipolysis to intermediate density lipoprotein (IDL; not shown) and then cholesterol-rich LDL. Peripheral tissues and liver take up LDL-derived cholesterol via the LDL receptor. HDL accepts cholesterol from peripheral tissue for transport back to the liver. The protein components of lipoproteins play key roles as structural elements, enzymes, enzyme cofactors, and ligands for cell surface receptors. For example, apoB is a ligand for the LDL receptor whereas apoA-I interacts with the scavenger receptor SR-BI. Recent mass spectrometric studies demonstrate that lipoproteins carry a diverse array of lower abundance proteins, raising the possibility that lipoproteins play previously unsuspected role in vascular disease and inflammation.