Lipoproteins lipid-protein interactions

T,he stoichiometric characterization of detergent-protein complexes has been the object of many studies over the past 30 years (6). Recent studies have placed more emphasis upon developing a molecular-kinetic description of the complex (2, 8). The importance of such descriptions lies in the fact that detergent-protein complexes can be considered as lipoprotein model systems. Indeed, virtually all conceptions of the microscopic nature of lipid-protein interactions are based on the properties of detergent-protein complexes (3). 

A similar type of interaction is thought to occur in membrane lipoprotein molecules. The problem in the latter studies is that the membrane apoproteins are not easily solubilized. If further information on the structure of biological membranes is required, then it is recommended that a recent book by Petty (1993) and one edited by Wirtz et al. (1993) be placed on a must reading list. An older, but very good, short review on lipid-protein interaction possibilities in membranes is one presented by Danielli (1982), who is widely recognized as a pioneer as well as a legend in this field. 

Net transfer of lipid occurs from the plasma to the erythrocyte membrane, presumably because of a shift in the equihbrium as the plasma lipoproteins become saturated with the excess cholesterol and phosphatidylcholine. This leads to membrane abnormalities and cholesterol-phospholipid ratios of up to 2 1. Changes in cellular physiology of the type referred to in section IV have also been reported [94,96,161]. These must reflect an alteration in lipid-protein interactions within the membranes. The molecular arrangement of the excessive amounts of cholesterol present in the cell membranes in diseased liver cells is not known. In model systems cholesterol is not present in molar amounts greater than 1 1. In liver disease a major change is in cellular morphology with the formation of abnormally shaped erythrocytes, as discussed earlier. 

Stoffel, W., Zierenberg, O., Tunggal, B. D., and Schreiber, E. (1974). Hoppe-Seyler s Z. Physiol. Chem. 355, 1381. 1 3C Nuclear Magnetic Resonance Spectroscopic Studies on Lipid-Protein Interactions in Human High-Density Lipoprotein (HDL) A Model of the IIDL Particle. 

On the contrary, the nutritional value of oxidized lipid-protein interaction products is substantially lower than that of the original lipoproteins. The main reason is the lower digestibility most covalent bonds formed in the interactions are not attacked by proteases under the conditions of digestion. The 6-amino group of bound lysine is particularly sensitive to interactions with carbonylic oxidation products (Janitz et al., 1990), and the resulting imine bonds substantially reduce the lysine availability. Lysine losses correlate with the increase in fluorescence. Other amino acids, such as tyrosine, tryptophan, and methionine, are also partially converted into unavailable products. Interaction products may be allergenic even when allergenic proteins have reacted (Doke et al., 1989). 

Kelley (1964) found that proteolysis completely destroyed 20 percent of the lipoprotein molecules in a low density lipoprotein solution. The lipid from these molecules was transferred to the remaining lipoprotein molecules which were less stable during storage but resistant to proteolytic enzyme attack. The additional lipid associated with modified lipoproteins may explain the enhanced ether extractability observed previously. These experiments indicate that lipid-protein interactions contribute to the stability of the molecular complex. 

Oncley, J. L. Lipid protein interactions, p. 1—17. In J. Folch-Pi and H. Baiter Brain Lipids and Lipoproteins, and the Leucodystrophies. Amsterdam Elsevier 1963. 

Morrisett, J.D., Jackson, R.L., and Gotto, A.M.,Jr., 1977, Lipid-protein interactions in the plasma lipoproteins, Biochim. Biophys. Acta, 427 93. 

Because of their relatively large hydrophobic surface area, apolipoproteins, in the absence of lipids, readily self-associate in aqueous solution (Stone and Reynolds, 1975 Vitello and Scanu, 1976). The rate of desorption of apolipoproteins from lipoprotein surfaces has not been studied systematically. Extensive studies of the reverse process, which is the assembly of lipid apoprotein complexes, have been conducted in considerable detail. The dynamic of lipid-protein interactions have been studied primarily with in vitro model systems. Analysis of the association of apolipoproteins with various phospholipid aggregates have provided important clues about the nature of the kinetically important steps in the transfer of apolipoproteins between lipoproteins (Pownall et al., 1977 1978a Massey et al., 1981a Mantulin et al., 1981). 

We hypothesize that a subtle drug protein interaction occurs when polar solvents are used to extract highly lipid soluble drugs from plasma. These solvents are capable of delipidizing lipoproteins. It is possible that, when delipidization occurs, the hydro-phobic region of that protein is exposed. The hydro-phobic region could then bind A9-THC and the binding... 

Lipoproteins are assembled in two organs, the small intestine and the liver. The lipoproteins assembled in the intestine contain the lipids assimilated from the diet. These lipoproteins, called chylomicrons, leave the enterocyte and enter the bloodstream via the Lymphatic system. The lipoproteins assembled in the liver contain lipids originating from the bloodstream and from de novo synthesis in the liver. The term de novo simply means "newly made from simple components" as opposed to "acquired from the diet" or "recycled from preexisting complex components." These lipoproteins, called very-low-dcnslty lipoproteins (VLDLs), are secreted from the liver into the bloodstream. The liver also synthesizes and secretes other Lipoproteins called high-density Lipoproteins (HDLs), which interact with the chylomicrons and VLDLs in the bloodstream and promote their maturation and function. The data in Table 6-4 show that chylomicrons contain a small proportion of protein, whereas HDLs have a relatively high protein content. Of greater interest is the identity and function of the proteins that constitute these particles. These proteins confer specific properties to lipoprotein particles, as detailed later in this chapter. 

Cholesterol, which is largely insoluble in aqueous m a, travels through the blood circulation in the form of Upoprotein complexes. The plasma lipoproteins are a family of globular particles that share common structural features. A core of hydrophobic lipid, principally triacylglycerols (triglycerides) and cholesterol esters, is surrounded by a hydrophilic monolayer of phospholipid and protein (the apolipoproteins) [1-3]. Lipid-apolipoprotein interactions, facihtated byi amphi-pathic protein helices that segregate polar from nonpolar surfaces [2,3], provide the mechanism by which cholesterol can circulate in a soluble form. In addition, the apolipoproteins modulate the activities of certain enzymes involved in Upoprotein metabolism and interact with specific cell surface receptors which take up Upopro-teins by receptor-mediated endocytosis. Differences in the Upid and apoUpoprotein compositions of plasma Upoproteins determine their target sites and classification based on buoyant density. 

Lipidomics Lipidomics means a systematic profiling of lipids and the entities that interact with lipids. Lipidomics may be extended to the genomics of lipid metabolism, understanding the biosynthesis pathways, lipoproteins, and proteins that interact and metabolize lipids. 

A specific type of interaction between lipids and proteins is found in lipoproteins which transport triglycerides and cholesteryl esters in the plasma of mammalians. The largest lipoproteins, chylomicrons with a diameter between 800 A and 5000 A, and very-low-density lipoproteins (VLDL), with a diameter of 300-800 A, resemble emulsion droplets with a core of non-polar lipid and a surface coat of phospholipids and proteins (cf. Brown et ai, 1981). A physical characterization of chylomicrons has been reported (Parks et al.y 1981). Most of the plasma cholesterol occurs in low-density lipoprotein (LDL) which is a particle with a diameter of 200 A. The core consists of almost pure cholesteryl esters and a surface coat of a phospholipid monolayer and four tetrahedrally arranged apoproteins (Gulik-Krzywicki et aly 1979). The smallest particle, high-density lipoprotein (HDL), is a kind of molecular lipid-protein complex. 

Apolipoproteins undergo changes in secondary protein structure when combined with phosphatidylcholine (Morrisett et al., 1977b). The circular dichroic spectrum and the blue-shifted tryptophan fluorescence spectrum are consistent with an amphipathic structure. Since lipoprotein lipase also can undergo hydrophobic association with phospholipids (Voyta et al., 1980), as indicated by blue-shifted tryptophan fluorescence, it seems probable that the interaction of the enzyme with the apoprotein activator at the lipid-water interface involves extensive lateral protein protein interactions (Smith and Scow, 1979). 

Lipids play an essential role in both the intrinsic and extrinsic pathways of proArombin activation. They enter the coagulation sequence after it has been initiated by surface contact and other protein interactions. There is no evidence that they initiate the coagulation process. The lipid is normally derived from the blood platelet where it probably exists as lipoprotein. It exerts a surface catalytic action on the plasma coagulation proteins with which it may bind in the presence of calciiun. The resulting complex could contain platelet liproprotein or its lipid moiety alone and may mediate prothrombin activation. 

When most lipids circulate in the body, they do so in the form of lipoprotein complexes. Simple, unesterified fatty acids are merely bound to serum albumin and other proteins in blood plasma, but phospholipids, triacylglycerols, cholesterol, and cholesterol esters are all transported in the form of lipoproteins. At various sites in the body, lipoproteins interact with specific receptors and enzymes that transfer or modify their lipid cargoes. It is now customary to classify lipoproteins according to their densities (Table 25.1). The densities are... 

---