Lipoprotein Structure and Function

Lipids in the bloodstream and other tissues are present in combination with other substances, rather than in the free state, since they are hydrophobic species in an essentially aqueous environment. For example, one of the simplest associations is between unesterified fatty acids and human serum albumin. Albumin has three high affinity sites characterized by hydrophobic regions incorporating charged amino acids in such a conformation as to interact with the carboxylate functionality of the fatty acid [35].

Lipoproteins are significantly more complex species that may be considered in general terms as water-soluble macromolecules providing a mechanism for the transport water-immiscible lipids in the blood stream and across cell boundaries. Molecular modeling studies based on compositional investigations have derived equations governing the structural distributions of lipid and protein species within the lipoprotein classes [36]. It has been further shown, by agreement of experimental observation with the compositional and modeling studies, that lipoproteins share an identical structural distribution of lipid species. The cholesterol ester and triglycerides are confined to an apolar spherical core whose size is dependent upon the diameter of the lipoprotein particle. This hydrophobic interior is surrounded by a 2.05 nm thick surface shell of closely packed cholesterol and phospholipid. The orientation of the phospholipid species' polar heads and the free hydroxyl group of cholesterol is such that they are aligned towards the external media to associate with the polar environment in the surrounding bloodstream. The fatty acid chains of the phospholipids and the sterol ring structure are in contact with each other and the hydrophobic core lipids.

It is stressed that due to the fluidity of the lipid components, this model should not be viewed as an immobile array of lipoprotein components. Rather, the proposed location of the lipid species is considered as a statistically predominant position, still permitting exchange reactions to occur, both within, and between the lipoprotein particles. Indeed, there is a continual dynamic flux of lipid species between the core and the surface - unesterified cholesterol enters the hydrophobic center and becomes a more significant core component with larger diameter particles. Conversely very small quantities of triglyceride and cholesterol esters are present in the surface monolayer [37].

The lipoprotein particles are also stabilized in the bloodstream by association with highly evolved proteins called apolipoproteins. Apolipoproteins assume conformations that include lipid-binding regions containing both hydrophilic and hydrophobic surfaces and enable binding to take place between the protein and phospholipids [38]. An even more specialized structure is illustrated by the conformation of the B apolipoproteins, which show a significantly lower proportion of amphipathic helices, and a higher content of ß structure. This feature produces larger hydrophobic regions where the protein can penetrate the particle, substituting for the surface monolayer and interacting directly with the core lipids [39]. However, the function of the protein is more than simply stabilization of the lipid components - rather they mediate particle metabolism by binding to specific cell receptors, and also act as cofactors for enzymes [40]. The curvature of the lipoprotein surface results in gaps between the polar head groups of the surface monolayer. The apolipoprotein moiety, largely unfolded, is able to fill the gaps and simultaneously interacts with the free cholesterol and masks it from the aqueous bloodstream.

Lipoproteins are not static species - they are involved in dynamic processes that alter their physical and chemical characteristics. Exchanges of lipids and protein moieties between different classes of lipoproteins during metabolic processes result in changes in the particles' physical characteristics. The stereochemistry and conformation of the associated apolipoproteins is affected by such interchanges which also influences interactions with receptor sites and enzymes in the body. Mutations and errors in the genetic coding for either the production or secretion, or conformational identity of the apolipoproteins, cell receptors or associated enzymes can result in various forms of dyslipidemia [41].