Phospholipids reverse transport

Reverse lipid transport is the movement of lipids, mainly cholesterol and phospholipids, from peripheral tissues, through the extracellular compartment, to the liver for catabolism. Unlike the forward transport of lipids, that involves mainly TG packaged into lipoproteins inside hepatic and intestinal cells, the cholesterol and phospholipids contributing to reverse transport are assembled into lipoproteins extracellularly, as the result of events in the plasma. 

HDL concentrations vary reciprocally with plasma triacylglycerol concentrations and directly with the activity of lipoprotein lipase. This may be due to surplus surface constituents, eg, phospholipid and apo A-I being released during hydrolysis of chylomicrons and VLDL and contributing toward the formation of preP-HDL and discoidal HDL. HDLj concentrations are inversely related to the incidence of coronary atherosclerosis, possibly because they reflect the efficiency of reverse cholesterol transport. HDL, (HDLj) is found in... 

Figure 25-5. Metabolism of high-density lipoprotein (HDL) in reverse cholesteroi transport. (LCAT, lecithinxholesterol acyltransferase C, cholesterol CE, cholesteryl ester PL, phospholipid A-l, apolipoprotein A-l SR-Bl, scavenger receptor B1 ABC-1, ATP binding cassette transporter 1.) Prep-HDL, HDLj, HDL3—see Table 25-1. Surplus surface constituents from the action of lipoprotein lipase on chylomicrons and VLDL are another source of preP-HDL. Hepatic lipase activity is increased by androgens and decreased by estrogens, which may account for higher concentrations of plasma HDLj in women.

Figure 26-5. Factors affecting cholesterol balance at the cellular level. Reverse cholesterol transport may be initiated by pre 3 HDL binding to the ABC-1 transporter protein via apo A-l. Cholesterol is then moved out of the cell via the transporter, lipidating the HDL, and the larger particles then dissociate from the ABC-1 molecule. (C, cholesterol CE, cholesteryl ester PL, phospholipid ACAT, acyl-CoA cholesterol acyltransferase LCAT, lecithinicholesterol acyltransferase A-l, apolipoprotein A-l LDL, low-density lipoprotein VLDL, very low density lipoprotein.) LDL and HDL are not shown to scale.

Hepatic steatosis usually is a result of excessive administration of carbohydrates and/or lipids, but deficiencies of carnitine, choline, and essential fatty acids also may contribute. Hepatic steatosis can be minimized or reversed by avoiding overfeeding, especially from dextrose and lipids.35,38 Carnitine is an important amine that transports long-chain triglycerides into the mitochondria for oxidation, but carnitine deficiency in adults is extremely rare and is mostly a problem in premature infants and patients receiving chronic dialysis. Choline is an essential amine required for synthesis of cell membrane components such as phospholipids. Although a true choline deficiency is rare, preliminary studies of choline supplementation to adult patients PN caused reversal of steatosis. 

The HDL lipids are removed from the circulation by a selective uptake and by an indirect pathway. The selective uptake of cholesterol esters from HDL into he-patocytes and steroidogenic cells is mediated by the binding of HDL to scavenger receptor B1 (SR-BI). This selective uptake by SR-BI may depend on the presence of cofactors such as HL, which hydrolyses phospholipids on the surface of both HDL and plasma membranes and thereby enables the flux of cholesteryl esters from the lipoprotein core into the plasma membrane [42]. The indirect pathway involves the enzyme CETP, which exchanges cholesteryl esters of a-HDL with triglycerides of chylomicrons, VLDL, IDL, and LDL. The a-HDL derived cholesteryl esters are therefore removed via the LDL-receptor pathway. The removal of excess cholesterol from the periphery and the delivery to the liver for excretion in the bile is termed reverse cholesterol transport. 

Muscle. Binding of drugs to components within the muscle may create the long-term storage of these compounds. Various agents may be actively transported into the muscle cell and may form reversible bonds to intracellular structures such as proteins, nucleoproteins, or phospholipids. An example is the antimalarial drug quinacrine. 

Bebawy et al. [186] demonstrated that CPZ (9) and vinblastine inhibited each other s transport in a human lymphoblastic leukemia cell line (CCRF-CEM/VLBioo). CPZ (9) reversed resistance to vinblastine but not to fluores-cently labeled colchicine and it increased resistance to colchicine. Colchicine was supposed to be transported from the inner leaflet of the membrane and vinblastine from the outer leaflet. CPZ (9) was assumed to be located in the inner membrane leaflet where it interacts with anionic groups of phospholipids and it may inhibit vinblastine transport via allosteric interactions. The authors concluded that transport of P-gp substrates and its modulation by CPZ (9) (or verapamil (79)) are dependent on substrate localization inside the membrane. Contrary to CPZ (9) location in the inner leaflet of the membrane, other modulators and substrates of P-gp were proved to be rather localized within the interface region of the membrane. The location of seven P-gp substrates and two modulators within neutral phospholipid bilayers was examined by NMR spectroscopy by Siarheyeva et al. [129]. The substrates and the modulators of P-gp were found in the highest concentrations within the membrane interface region. The role of drug-lipid membrane interactions in MDR and its reversal was reviewed in detail elsewhere [53,187]. 

Yazdanyar A, Yeang C, Jiang XC (2011) Role of phospholipid transfer protein in high-density lipoprotein-mediated reverse cholesterol transport. Curr Atheroscler Rep 13 242-248... 

Paramagnetic analogs of phospholipids have also been used to investigate lipid transport phenomena in model membrane systems (R.D. Komberg, 1971) and in biological membranes. Representative structures are shown in Fig. 2. Several of these spin-labeled lipid analogs that are modified in the fatty acid chain can be readily and reversibly transferred... 

As far as HDL levels and metabolism are concerned, one result of the LCAT- and transfer protein-catalyzed reactions is the production of a dynamic spectrum of particles with a wide range of sizes and lipid compositions (Chapter 19). Nascent HDL particles contain mostly apo A1 and phospholipids, and undergo modulation and maturation in the circulation. For instance, the unesterified cholesterol incorporated into plasma HDL is converted to cholesteryl esters by LCAT, creating a concentration gradient of cholesterol between HDL and cell membranes, which is required for efficient cholesterol efflux from cells to HDL. In addition, cholesteryl ester transfer protein transfers a significant amount of HDL cholesteryl ester to VLDL, IDL, and LDL for further transport, primarily to the liver. Thus, a substantial fraction of cell-derived cholesterol is delivered as part of HDL indirectly to the liver via hepatic endocytic receptors for IDL and LDL this process is termed reverse cholesterol transport . However, receptor-mediated delivery of HDL cholesterol to cells is fundamentally different from the classic LDL receptor-mediated endocytic pathway, as described in Section 7.3.2. 

Prothrombin sorption is reversible and calcium-dependent. The prothrombin association constant K is dependent on the surface concentration of protein and on the composition of the phospholipid bilayers, indicating interacting binding sites. The initial rate of prothrombin adsorption is transport limited in all conditions studied. Values of the sorption rate constants k and are dependent on the surface concentration. The rate of adsorption decreases for higher surface concentration and the intrinsic values of... 

HDL is synthesized in the liver and is secreted as a phospholipid/apoprotein disk. During transit in the blood, HDL acts as a sink for cholesterol. Hepatocytes have receptors that bind cholesterol-rich HDL particles, thus completing a cycle of transport of cholesterol from the liver to the periphery and back again to the liver. The latter half of this metabolic loop is called reverse cholesterol transport. 

The promotion of cholesterol efflux from cells could be the first step in reverse cholesterol transport. In their experiments using cholesterol-loaded human skin fibroblasts, Stein and colleagues [31] showed a significant enhancement of cholesterol efflux by Apo A-IV/phospholipid complexes. It is not yet fully understood how apoproteins promote cellular cholesterol efflux. Evidence is accumulating that a specific receptor-mediated process is involved. Thus far, it has been shown that Apo A-IV binds to cells and membrane preparations from different species. Ghiselli et al. [14] concluded from their experiments that rat Apo A-IV/DMPC complexes bound specifically in a saturable manner to rat liver membranes. Along the same line, Dvorin... 

In addition, cholesterol accumulation in macrophages, mediated by modified lipoproteins (e. g., acetylated low-density lipoprotein, AcLDL), stimulates these cells to synthesize and secrete apolipoprotein (Apo) E/phospholipid discs. During the intraplasmatic cholesterol esterification process mediated by lecithinxholesterol acyltransferase (LCAT), HDL are assumed to incorporate unesterified cholesterol from the cell surface and Apo E from secreted Apo E/phospholipid discs and thereby mediate reverse cholesterol transport from peripheral cells back to the liver. The resulting cholesteryl ester- and Apo E-enriched HDLi are transported to the liver where they may be recognized by a hepatic Apo E receptor. 

---