Publisher Summary This chapter focuses on the role of apoE in lipoprotein metabolism and the most completely described function of the protein. Apolipoprotein E (apoE) is one of the best characterized in terms of its structural and functional properties. Plasma apolipoproteins regulate lipoprotein metabolism and control the transport and redistribution of lipids among tissues and cells. Apolipoproteins can perform one of three major roles because of their ability to bind lipid. First, apolipoproteins stabilize the pseudomicellar structure of lipoprotein particles. Second, apolipoproteins can act as cofactors or activators of various enzymes or lipid transfer proteins that participate in the metabolism of “remodeling” of lipoproteins as they circulate in plasma. A third function of plasma apolipoproteins-one that is restricted to apoB100 and ApoE- is to serve as a ligand for cell surface lipoprotein receptors. The three-dimensional structure of a 22-kDa fragment of human apoE is solved by X-ray crystallography; the relation of this structure to the role of apoE in lipoprotein metabolism is discussed, together with a critical and extensive examination of the chemistry and biology of this apolipoprotein, which plays such a central role in lipoprotein metabolism. Apolipoprotein E has three major isoform in the human population, which affect lipoprotein metabolism differently, resulting in different levels of the plasma lipoproteins. The role of apoE as a cofactor in lipolytic processing of triglyceride-rich lipoproteins, and the role of apoE in the reverse cholesterol transport process are described.

Apolipoprotein E: Structure-Function Relationships

The human apoCs (ie, apoC1, apoC2, and apoC3) are often portrayed as members of 1 consistent protein family because of their similar distributions among lipoprotein classes, their low molecular weights, and coincident purification. The human apoCs are protein constituents of chylomicrons, VLDL, and HDL. In comparison with the intensely studied apoE, apoB, and apoA1, which play important roles in the development of hyperlipidemia and atherosclerosis, only modest attention has been paid so far to the roles of the apoCs in lipoprotein metabolism. Many of the studies regarding the functional properties of apoCs have been hampered by methodological problems dealing with purification, quantification, and their poorly understood association with hyperlipidemia and other lipoprotein disorders. In the past few years, however, new insights into the metabolic properties of apoCs have been provided, in particular by the technologies of transgenesis and gene targeting in mice.

Role of ApoCs in Lipoprotein Metabolism Functional Differences Between ApoC1, ApoC2, and ApoC3

The structure of truncated human apolipoprotein A-I (apo A-I), the major protein component of high density lipoprotein, has been determined at 4-Å resolution. The crystals comprise residues 44–243 (exon 4) of apo A-I, a fragment that binds to lipid similarly to intact apo A-I and that retains the lipid-bound conformation even in the absence of lipid. The molecule consists almost entirely of a pseudo-continuous, amphipathic α-helix that is punctuated by kinks at regularly spaced proline residues; it adopts a shape similar to a horseshoe of dimensions 125 × 80 × 40 Å. Four molecules in the asymmetric unit associate via their hydrophobic faces to form an antiparallel four-helix bundle with an elliptical ring shape. Based on this structure, we propose a model for the structure of apo A-I bound to high density lipoprotein.

https://www.pnas.org/content/pnas/94/23/12291.full.pdf

Crystal structure of truncated human apolipoprotein A-I suggests a lipid-bound conformation.

Regulation of hepatic secretion of apolipoprotein B-containing lipoproteins: information obtained from cultured liver cells.

The concentration, composition, shape, and size of plasma high-density lipoprotein (HDL) are determined by numerous proteins that influence its biogenesis, remodeling, and catabolism. The discoveries of the HDL receptor (scavenger receptor class B type I, SR-BI) and the ABCA1 (ATP-binding cassette transporter A1) lipid transporter provided two missing links that were necessary to understand the biogenesis and some of the functions of HDL. Existing data indicate that functional interactions between apoA-I and ABCA1 are necessary for the initial lipidation of apoA-I. Through a series of intermediate steps, lipidated apoA-I proceeds to form discoidal HDL particles that can be converted to spherical particles by the action of lecithin:cholesterol acyltransferase (LCAT). Discoidal and spherical HDL can interact functionally with SR-BI and these interactions lead to selective lipid uptake and net efflux of cholesterol and thus remodel HDL. Defective apoA-I/ABCA1 interactions prevent lipidation of apoA-I that is necessary for the formation of HDL particles. In the same way, specific mutations in apoA-I or LCAT prevent the conversion of discoidal to spherical HDL particles. The interactions of lipid-bound apoA-I with SR-BI are affected in vitro by specific mutations in apoA-I or SR-BI. Furthermore, deficiency of SR-BI affects the lipid and apolipoprotein composition of HDL and is associated with increased susceptibility to atherosclerosis. Here we review the current status of the pathway of HDL biogenesis and mutations in apoA-I, ABCA1, and SR-BI that disrupt different steps of the pathway and may lead to dyslipidemia and atherosclerosis in mouse models. The phenotypes generated in experimental mouse models for apoA-I, ABCA1, LCAT, SR-BI, and other proteins of the HDL pathway may facilitate early diagnosis of similar phenotypes in the human population and provide guidance for proper treatment.

S Datta

Papers

The apolipoprotein multigene family: biosynthesis, structure, structure-function relationships, and evolution.