Phospholipid transfer protein activity in two cholestatic patients
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CONTEXT: Plasma phospholipid transfer protein mediates the transfer of phospholipids from triglyceride-rich lipoproteins, very low density lipoproteins and low density lipoproteins to high density lipoproteins, a process that is also efficient between high density lipoprotein particles. It promotes a net movement of phospholipids, thereby generating small lipid-poor apolipoprotein AI that contains particles and subfractions that are good acceptors for cell cholesterol efflux. CASE REPORT: We measured the activity of plasma phospholipid transfer protein in two cholestatic patients, assuming that changes in activity would occur in serum that was positive for lipoprotein X. Both patients presented severe hypercholesterolemia, high levels of low density lipoprotein cholesterol and, in one case, low levels of high density lipoprotein cholesterol and high levels of phospholipid serum. The phospholipid transfer activity was close to the lower limit of the reference interval. To our knowledge, this is the first time such results have been presented. We propose that phospholipid transfer protein activity becomes reduced under cholestasis conditions because of changes in the chemical composition of high density lipoproteins, such as an increase in phospholipids content. Also, lipoprotein X, which is rich in phospholipids, could compete with high density lipoproteins as a substrate for phospholipid transfer protein.Keywords:
Phospholipid transfer protein
Intermediate-density lipoprotein
High-density lipoprotein
Reverse cholesterol transport
Lipoprotein(a)
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Intermediate-density lipoprotein
Reverse cholesterol transport
Cholesterylester transfer protein
Low-density lipoprotein
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Chylomicron
Intermediate-density lipoprotein
Plasma lipoprotein
Cholesterylester transfer protein
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In atherosclerosis, cholesterol accumulates in the vessel wall, mainly in the form of low-density lipoprotein (LDL). Macrophages of the vessel wall scavenge cholesterol, which leads to formation of lipid-laden foam cells. Several pathways and transporter proteins are involved in the regulation of cholesterol balance in macrophages. High plasma levels of high-density lipoprotein (HDL) protect against atherosclerosis, as HDL particles are able to accept cellular cholesterol and transport it to the liver for excretion in a process called reverse cholesterol transport. Phospholipid transfer protein (PLTP) remodels HDL particles in the circulation, generating preβ-HDL and large fused HDL particles. In addition, PLTP maintains plasma HDL levels by facilitating the transfer of post-lipolytic surface remnants of triglyceride-rich lipoproteins to HDL. Reportedly, PLTP has both antiatherogenic and proatherogenic properties. Most of the cholesteryl ester transfer protein (CETP) in plasma is bound to HDL particles and CETP is also involved in the remodeling of HDL particles. CETP enhances the heteroexchange of cholesteryl esters in HDL particles for triglycerides in LDL and very low-density lipoprotein (VLDL). The role of CETP in the development of atherosclerosis is controversial. The aim of this thesis project was to study the importance of endogenous PLTP in the removal of cholesterol from macrophage foam cells by using macrophages derived from PLTP-deficient mice, determine the effect of macrophage-derived PLTP on the development of atherosclerosis by using bone marrow transplantation, and clarify the role of the two forms of PLTP, active and inactive, in the removal of cholesterol from foam cells. In addition, the ability of CETP to protect HDL against the action of chymase in CETP-HDL complexes was studied. Furthermore, cholesterol efflux from macrophages derived from lowand high-HDL subjects was studied. Finally, cholesterol efflux potential of sera obtained from the study subjects was compared. In this thesis project it was demonstrated that the absence of PLTP in macrophages derived from PLTP-deficient mice decreased cholesterol efflux mediated by ATP-binding cassette transporter A1 (ABCA1). The bone marrow transplantation studies demonstrated that selective deficiency of PLTP in macrophages decreased the size of atherosclerotic lesions and caused major changes in serum lipoprotein levels and PLTP activity. It was further demonstrated that the active form of PLTP can enhance cholesterol efflux from macrophage foam cells. Both preβ-HDL and large fused HDL particles enriched with apoE and phospholipids were effective in cholesterol efflux. Besides PLTP, also CETP may enhance the reverse cholesterol transport process, as association of CETP with reconstituted HDL (rHDL) particles prevented chymase-dependent proteolysis of discoidal rHDL and preserved their cholesterol efflux potential. Finally, monocyte macrophages isolated from either lowor high-HDL subjects displayed similar cholesterol efflux to exogenous acceptors. However, serum from high-HDL subjects promoted more efficient cholesterol efflux than did serum from low-HDL subjects. The observed difference was most probably due to differences in the distribution of HDL subpopulations in low-HDL and high-HDL subjects. The results of this thesis project indicate that both PLTP and CETP can remodel HDL as a cholesterol acceptor, which affects the removal of cholesterol from foam cells present in the vessel wall.
Cholesterylester transfer protein
Phospholipid transfer protein
Reverse cholesterol transport
Cholesteryl ester
Intermediate-density lipoprotein
High-density lipoprotein
Foam cell
Sterol O-acyltransferase
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Intermediate-density lipoprotein
Cholesterylester transfer protein
Cholesteryl ester
Phospholipid transfer protein
High-density lipoprotein
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It is known that plasma phospholipid transfer protein (PLTP) activity influences lipoprotein metabolism. The liver is one of the major sites of lipoprotein production and degradation, as well as of PLTP expression. To address the impact of liver-expressed PLTP on lipoprotein metabolism, we created a mouse model that expresses PLTP in the liver acutely and specifically, with a PLTP-null background. This approach in mouse model preparations can also be used universally for evaluating the function of many other genes in the liver. We found that liver PLTP expression dramatically increases plasma levels of non–high-density lipoprotein (HDL) cholesterol (2.7-fold, P < 0.0001), non-HDL phospholipid (2.5-fold, P < 0.001), and triglyceride (51%, P < 0.01), but has no significant influence on plasma HDL lipids compared with controls. Plasma apolipoprotein (apo)B levels were also significantly increased in PLTP-expressing mice (2.2-fold, P < 0.001), but those of apoA-I were not. To explore the mechanism involved, we examined the lipidation and secretion of nascent very low-density lipoprotein (VLDL), finding that liver PLTP expression significantly increases VLDL lipidation in hepatocyte microsomal lumina, and also VLDL secretion into the plasma. Conclusion : It is possible to prepare a mouse model that expresses the gene of interest only in the liver, but not in other tissues. Our results suggest, for the first time, that the major function of liver PLTP is to drive VLDL production and makes a small contribution to plasma PLTP activity. (HEPATOLOGY 2012)
Phospholipid transfer protein
Lipid-anchored protein
High-density lipoprotein
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Cholesterylester transfer protein
Phospholipid transfer protein
Sterol O-acyltransferase
Cholesteryl ester
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Phospholipid transfer protein
Chain (unit)
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Plasma lipoproteins are a polydisperse collection of particles which range in diameter from 7 to 160 nm. These lipoproteins particles have been classified according to methods of separation1. One system, based on density, divides the lipoproteins into five classes: chylomicrons (ρ < 0.95), very-low-density lipoproteins (VLDL, 0.95 < ρ < 1.006), intermediate-density lipoproteins (IDL, 1.006 < ρ < 1.019), low-density lipoproteins (LDL, 1.019 < ρ < 1.063) and high-density lipoproteins (HDL, 1.063 < ρ < 1.210). Another popular system, based on electrophoretic mobility, divides the lipoproteins into those which remain at the origin (chylomicrons) and those which migrate in the beta region (β-lipoproteins), pre-beta regions (pre-β-lipoproteins) and alpha region (α-lipoproteins). There is a partial correspondence of LDL with β-lipoproteins, of VLDL with pre-β-lipoproteins and of HDL with α-lipoproteins. Each lipoprotein is a macromolecular complex of lipids (including triglyceride, cholesterol, cholesterol ester, phospholipid and others) and apolipoproteins (A-I, A-II, A-IV, B, C-I, C-II, C-III, D, E, F, H), arranged such that the lipoprotein particle is relatively soluble in the aqueous plasma environment.
Chylomicron
Intermediate-density lipoprotein
Plasma lipoprotein
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