Core Of LDL Research Articles

Apolipoprotein F concentration, activity, and the properties of LDL controlling ApoF activation in hyperlipidemic plasma

Apolipoprotein F (ApoF) modulates lipoprotein metabolism by selectively inhibiting cholesteryl ester transfer protein activity on LDL. This ApoF activity requires that it is bound to LDL. How hyperlipidemia alters total plasma ApoF and its binding to LDL are poorly understood. In this study, total plasma ApoF and LDL-bound ApoF were quantified by ELISA (n = 200). Plasma ApoF was increased 31% in hypercholesterolemic plasma but decreased 20% in hypertriglyceridemia. However, in donors with combined hypercholesterolemia and hypertriglyceridemia, the elevated triglyceride ameliorated the rise in ApoF caused by hypercholesterolemia alone. Compared with normolipidemic LDL, hypercholesterolemic LDL contained ∼2-fold more ApoF per LDL particle, whereas ApoF bound to LDL in hypertriglyceridemia plasma was <20% of control. To understand the basis for altered association of ApoF with hyperlipidemic LDL, the physiochemical properties of LDL were modified in vitro by cholesteryl ester transfer protein ± LCAT activities. The time-dependent change in LDL lipid composition, proteome, core and surface lipid packing, LDL surface charge, and LDL size caused by these factors were compared with the ApoF binding capacity of these LDLs. Only LDL particle size correlated with ApoF binding capacity. This positive association between LDL size and ApoF content was confirmed in hyperlipidemic plasmas. Similarly, when in vitro produced and enlarged LDLs with elevated ApoF binding capacity were incubated with LPL to reduce their size, ApoF binding was reduced by 90%. Thus, plasma ApoF levels and the activation status of this ApoF are differentially altered by hypercholesterolemia and hypertriglyceridemia. LDL size is a key determinate of ApoF binding and activation.

Lipid Transfer Mechanism of CETP between HDL and LDL: A Coarse-Grained Simulation Study

Cholesteryl ester transfer protein (CETP) mediates the bidirectional exchange of cholesteryl esters (CEs) and triglycerides between HDL and LDL (1)⁠. Animal models along with early clinical studies have demonstrated that the impairment of CETP's functionality is important for the efficient treatment of cardiovascular diseases. Despite the pharmacological interest, CETP's lipid transfer mechanism is poorly understood. Recent cryo-electron microscopy studies suggested that CETP penetrates its N-and C-terminal β-barrel domains into HDL and LDL respectively to form a ternary complex (2)⁠. Further it was proposed that the hydrophobic tunnel of CETP can simultaneously interact with the core of HDL and LDL for continuous lipid exchange. However, the detailed lipid transfer process is still inconclusive. In this study, we employed coarse-grained molecular dynamics simulations to illuminate the lipid transfer mechanism of CETP in HDL-CETP-LDL ternary complex. The extent of penetration of CETP into HDL and LDL in our ternary complex model corroborated well with the experimental findings. Further, the results demonstrated that the ejection of C-terminal plug-in phospholipid (PLC) and subsequently the diffusion of CETP-bound CEs into LDL droplet through PLC opening. A detailed analysis on interactions of PLC pocket lining residues with the discharged lipids revealed residues with significant role in CE transfer. The detailed mechanism of lipid transfer by CETP as explored in this study might help designing future CETP research and subsequent CETP therapeutics.

Abstract 422: Oxidation of Ldl by Iron at Lysosomal pH Leads to the Formation of Tryptophan Radicals Which Are Not Inhibited by Probucol

The LDL oxidation hypothesis proposes that cells oxidise LDL in arterial interstitial fluid and macrophages take it up rapidly, becoming foam cells. LDL oxidation is inhibited by interstitial fluid, however, and large clinical trials have shown no protection by antioxidants, including probucol. We therefore proposed that LDL might be nonoxidatively modified and aggregated by enzymes, such as sphingomyelinase, in interstitial fluid, rapidly phagocytosed by macrophages and oxidised by iron inside lysosomes, which have a pH of about 4.5 (Wen &amp; Leake, 2007, Circ. Res. 100 , 1337). Tryptophan in apoB-100 might be involved in the initiation of LDL oxidation by copper (Giessauf et al ., 1995, Biochim. Biphys. Acta 1256 , 221). We investigated the mechanisms of LDL oxidation by iron at lysosomal pH. LDL (50 μg LDL protein/ml) was oxidised by FeSO 4 or FeCl 3 (5 μM) at 37 °C in 150 mM NaCl/10 mM sodium acetate buffer, pH 4.5. Lipid oxidation was measured in terms of conjugated dienes at 234 nm and tryptophan oxidation by the loss of fluorescence (Ex/Em 282/331 nm). Unexpectedly, both lipid peroxidation and loss of tryptophan fluorescence was faster with Fe 2+ than Fe 3+ . Interestingly, probucol did not inhibit lipid oxidation for about 100 min with Fe 2+ at pH 4.5 and did not prevent the loss of tryptophan fluorescence.In contrast, probucol inhibited entirely the initial oxidation of LDL by Cu 2+ at pH 7.4. Fe 2+ was completely consumed during 100 min of LDL oxidation at pH 4.5, as shown using bathophenanthroline and might generate superoxide radicals. Superoxide radicals would protonate at pH 4.5 to produce highly reactive and lipid-soluble hydroperoxyl radicals, which might abstract hydrogen atoms form lipids and tryptophan. As probucol would be expected to scavenge lipid radicals in the surface monolayer of LDL particles (Bard et al ., 1994, J, Pharm. Pharmacol. 46 , 797), the initial oxidation of LDL at pH 4.5 would be expected to happen in the core of LDL where probucol has limited excess. We propose the following mechanism for LDL oxidation by Fe 2+ at lysosomal pH. Fe 2+ + O 2 → Fe 3+ + O 2 •- O 2 •- + H + ↔ HO 2 • (pK a 4.8) HO 2 • + TrpH → Trp • + H 2 O 2 Trp • + O 2 → TrpOO • HO 2 • + LH → L • + H 2 O 2 L • + O 2 → LOO • This might help to explain why probucol was not beneficial in the clinical trials.

LDL particle core enrichment in cholesteryl oleate increases proteoglycan binding and promotes atherosclerosis

Several studies in humans and animals suggest that LDL particle core enrichment in cholesteryl oleate (CO) is associated with increased atherosclerosis. Diet enrichment with MUFAs enhances LDL CO content. Steroyl O-acyltransferase 2 (SOAT2) is the enzyme that catalyzes the synthesis of much of the CO found in LDL, and gene deletion of SOAT2 minimizes CO in LDL and protects against atherosclerosis. The purpose of this study was to test the hypothesis that the increased atherosclerosis associated with LDL core enrichment in CO results from an increased affinity of the LDL particle for arterial proteoglycans. ApoB-100-only Ldlr(-/-) mice with and without Soat2 gene deletions were fed diets enriched in either cis-MUFA or n-3 PUFA, and LDL particles were isolated. LDL:proteogylcan binding was measured using surface plasmon resonance. Particles with higher CO content consistently bound with higher affinity to human biglycan and the amount of binding was shown to be proportional to the extent of atherosclerosis of the LDL donor mice. The data strongly support the thesis that atherosclerosis was induced through enhanced proteoglycan binding of LDL resulting from LDL core CO enrichment.

Chiral porphyrazine near-IR optical imaging agent exhibiting preferential tumor accumulation

A chiral porphyrazine (pz), H(2)[pz(trans-A(2)B(2))] (247), has been prepared that exhibits preferential in vivo accumulation in the cells of tumors. Pz 247 exhibits near-infrared (NIR) emission with lambda > 700 nm in the required wavelength range for maximum tissue penetration. When MDA-MB-231 breast tumor cells are treated with 247, the agent shows strong intracellular fluorescence with an emission maximum, 704 nm, which indicates that it localizes within a hydrophobic microenvironment. Pz 247 is shown to associate with the lipophilic core of LDL and undergo cellular entry primarily through receptor-mediated endocytosis accumulating in lysosomes. Preliminary in vivo studies show that 247 exhibits preferential accumulation and retention in the cells of MDA-MB-231 tumors subcutaneously implanted in mice, thereby enabling NIR optical imaging with excellent contrast between tumor and surrounding tissue. The intensity of fluorescence from 247 within the tumor increases over time up to 48 h after injection presumably due to the sequestration of circulating 247/LDL complex by the tumor tissue. As the need for cholesterol, and thus LDL, is elevated in highly proliferative tumor cells over nontumorigenic cells, 247 has potential application for all such tumors.

Lipid fluidity at different regions in LDL and HDL of β-thalassemia/Hb E patients

Atherosclerosis-related vascular complications in β-thalassemia/hemoglobin E (β-thal/Hb E) patients may result from iron induced oxidation of lipoproteins. To identify the specific site of oxidative damage, changes in lipid fluidity at different regions in LDL and HDL particle were investigated using two fluorescence probes and two ESR spin probes. The magnitude of increased lipid fluidity in thalassemic lipoproteins was dependent on the location of the probes. In hydrophobic region, the rotational correlation times for 16-doxyl stearic acid and DPH anisotropy were markedly changed in LDL and HDL of the patients. In the surface region, there was only a slight change in the order parameter ( S) for 5-doxyl stearic acid and TMA-DPH anisotropy. Lipid fluidity at the core of LDL and HDL showed good correlation with oxidative stress markers, the ratio of CL/CO, and the level of α-tocopherol, suggesting that hydrophobic region of thalassemic lipoprotein was a target site for oxidative damage.

Synergistic induction of D2 apoptosis, mt depolymerizing action, angioinhibition and antimetastatic action against radio- and chemoresistant metastatic hormone refractory prostate ca (HRPC) overexpressing bcl-2,MMP-9 and MDR-1 after photodynamic treatment with porfimer sodium associated LDL and vinorelbine tartrate (VRL)

Synergistic induction of D2 apoptosis, mt depolymerizing action, angioinhibition and antimetastatic action against radio- and chemoresistant metastatic hormone refractory prostate ca (HRPC) overexpressing bcl-2,MMP-9 and MDR-1 after photodynamic treatment with porfimer sodium associated LDL and vinorelbine tartrate (VRL)

Combined data from LDL composition and size measurement are compatible with a discoid particle shape

The size of LDL is usually reported as particle diameter, with the implicit assumption that it is a spherical particle. On the other hand, data obtained by cryoelectron microscopy and crystallographic analysis suggest that LDL shape may be discoid. We have investigated LDL particle geometry by combining data on LDL lipid composition with size measurement. The mean LDL diameter of 160 samples was measured by high-performance gel-filtration chromatography (HPGC), and particle volume was calculated from its lipid composition. Assuming a spherical shape, diameters calculated from volume correlated poorly with values obtained by HPGC (R(2) = 0.36). Assuming a discoid shape, particle height was calculated from volume and HPGC diameter. Diameter (20.9 +/- 0.5 nm) and height (12.1 +/- 0.8 nm) were not significantly related to each other (r = 0.14, P = 0.09) and accounted for 23% and 77%, respectively, of the variation in particle volume. In multivariate regression models, LDL core lipids were the main determinants of height (R(2) = 0.83), whereas free cholesterol in the shell, which contributes only 5-9% to LDL mass, was the main determinant of diameter (R(2) = 0.54). We conclude that combined data from composition and size measurements are compatible with a discoid particle shape and propose a structural model for LDL in which free cholesterol plays a major role in determining particle shape and diameter.

The physical state of the LDL core influences the conformation of apolipoprotein B-100 on the lipoprotein surface

We assessed the influence of temperature on the secondary structure of apolipoprotein B-100 (apoB) in normal low-density lipoprotein (N-LDL) and triglyceride-rich LDL (T-LDL). Gradual heating from 7°C to the phase-transition temperature of the lipoprotein core (∼28°C and ∼15°C for N-LDL and T-LDL, respectively) gradually altered the secondary structure of apoB, while further heating from the phase-transition temperature to 45°C had no additional effect. Above the phase-transition temperature of the core, the apoBs of N-LDL and T-LDL had a similar secondary structure. These results indicate that the conformation of apoB on the LDL surface depends strongly on the physical state of the lipoprotein core, and less on the lipid composition of the core per se.

Variability in alpha-tocopherol antioxidant activity in the core and surface layers of low- and high-density lipoproteins.

The effect of alpha-tocopherol enrichment of low- and high-density lipoproteins on Cu(2+)-catalyzed lipid peroxidation in the hydrophobic core and in the hydrophilic envelope of lipoproteins was investigated by using two pyrene derivatives, namely, cholesteryl pyrenyl hexanoate (P6Chol) and pyrene dodecanoyl sulfatide (P12CS). The progressive decrease in fluorescence of P6Chol was used to monitor lipid peroxidation in the core of LDL and HDL, whereas that of P12CS was used to follow lipid peroxidation in the envelope of both lipoproteins. alpha-Tocopherol enrichment of LDL and HDL was obtained by incubating blood plasma at 37 degrees C with different concentrations of the vitamin (25-500 microM) before lipoprotein separation. The incorporation of alpha-tocopherol in LDL and HDL presents a progressive, time-dependent increase up to 200 microM alpha-tocopherol, then a plateau up to 500 microM. In the envelopes, the added tocopherol causes a great decrease in the rate of peroxidation and a dramatic increase in the latency phase in both lipoproteins. In the cores the lengthening of latency phase resulting from alpha-tocopherol enrichment was by far greater in LDL than in HDL, and the decrease in the rate of peroxidation in both lipoproteins was less than in the envelopes.

In vitro production of β-very low density lipoproteins and small, dense low density lipoproteins in mildly hypertriglyceridemic plasma: role of activities of lecithin:cholester acyltransferase, cholesterylester transfer proteins and lipoprotein lipase

As a model for the formation of β-very low density lipoproteins (VLDL) and small, dense LDL by the intraplasma metabolic activities in vivo, lipoproteins in fresh plasma were interacted in vitro with endogenous lecithin:cholesterol acyltransferase (LCAT) and cholesterylester transfer proteins (CETP) and subsequently with purified lipoprotein lipase (LpL). The LCAT and CETP reactions in a mildly hypertriglyceridemic (HTG) plasma at 37°C for 18 h resulted in (1) esterification of about 45% plasma unesterified cholesterol (UC), (2) a marked increase in cholesterylester (CE) (+129%) and a decrease in triglyceride (TG) (−45%) in VLDL, and (3) a marked increase of TG (+341%) with a small net decrease of CE (−3.6%) in LDL, causing a significant alteration in the TG/CE of VLDL (from 8.0 to 1.9) and of LDL (from 0.20 to 0.93). The LDL in LCAT and CETP-reacted plasma is larger and more buoyant than that in control plasma. In vitro lipolysis of control and LCAT and CETP-reacted plasma by LpL, which hydrolyzed >90% of VLDL-TG and about 50–60% of LDL-TG, converted most of VLDL in control plasma (>85%) but less than half (40%) of VLDL in LCAT and CETP-reacted plasma into the IDL–LDL density fraction and transformed the large, buoyant LDL in the LCAT and CETP-reacted plasma into particles smaller and denser than those in the control plasma. The remnants that accumulated in the VLDL density region of the postlipolysis LCAT and CETP-reacted plasma contained apo B-100 and E but little or no detectable apo Cs and consisted of particles having pre- β and β-electrophoretic mobilities. The inhibition of LCAT during incubation of plasma, which lessened the extent of alteration in VLDL and LDL core lipids, increased the extent of lipolytic removal of VLDL from the VLDL density region but lowered the extent of alteration in the size and density of LDL. The LCAT, CETP and/or LpL-mediated alterations in the density of LDL in normolipidemic fasting plasma were less pronounced than that in mildly HTG plasma, but they became highly pronounced upon increase of its TG-rich lipoprotein level by the addition of preisolated VLDL or by the induction of postprandial lipemia. Although the effect of LCAT, CETP and LpL reactions in non-circulating plasma in vitro may be different from that in vivo, the above data suggests that the plasma TG-rich lipoprotein level and the extent of intraplasma LCAT, CETP, LpL and likely hepatic lipase (HL) reactions in vivo may play a role in determining the LDL phenotype.

Molecular acoustic as a new tool for the study of biophysical properties of lipoproteins

The method of measurement of velocity and absorption of ultrasound at a fixed frequency (7.2 MHz) and measurement of density were used to study the physical properties of high- (HDL 3) and low- (LDL) density lipoproteins. We found substantial changes in velocity number [ u] and absorption number [αλ] on temperature, which reflect structural changes in the hydrophobic core of LDL at the thermotropic-phase transition. The absorption number revealed broad changes in temperature for both classes of lipoproteins (LP). The density of LP also depends on temperature but in considerably less degree than the acoustic parameters. The values of acoustic parameters were determined, showing that LDL and HDL 3 greatly differ with respect to adiabatic compressibility.

Pyrene lipids as markers of peroxidative processes in different regions of low and high density lipoproteins

Three different pyrene derivatives, pyrene decanoyl phosphatidylcholine (P 10PC), pyrene dodecanoyl sulfatide (P 12CS) and cholesteryl pyrenyl hexanoate (P 6Chol), were used to follow lipid peroxidation in low and high density lipoproteins. Probe-labelled lipoproteins were subjected to Cu 2+ catalyzed peroxidation. In all cases the fluorescence of the probes progressively decreased due to the involvement of pyrene in the peroxidative reaction. Thus, we used the fluorescence decrease of P 6Chol to monitor the lipid peroxidation in the hydrophobic core of LDL and HDL, and that of the amphipatic probes, P 10PC and P 12CS, to follow lipid peroxidation in the envelope of both lipoproteins. The possibility of following lipid peroxidation in individual lipoprotein regions could lead to more detailed information on the oxidative modifications that play an important role in the altered cholesterol homeostasis involved in the formation of atherosclerotic lesions. No differences were observed in the peroxidation kinetics of the hydrophobic core of HDL and LDL monitored with P 6Chol. On the contrary kinetics obtained with P 10PC and P 12CS demonstrated the HDL envelope to be more susceptible to Cu 2+-dependent lipid peroxidation than that of the LDL. This could be due to a greater radical generating capacity of the HDL envelope and can be explained on the basis of low vitamin E levels and large amounts of polyunsaturated fatty acids esterified on phospholipids determined in HDL, and on literature evidence that indicates HDL as the principal vehicle of circulating plasma lipid peroxides.

Structural changes of lipoprotein lipids by 1H NMR

A new procedure for detecting structural changes of lipoprotein lipids is introduced and applied to study native low (LDL) and high density lipoprotein (HDL) particles. The method involves lineshape fitting analyses of specific resonances in proton nuclear magnetic resonance spectra together with numerical derivation of the obtained intensity curves with respect to temperature. In addition to the well-known phase transition of the LDL core cholesterol esters, a novel structural change was revealed in the phospholipid monolayer of both native LDL and HDL particles. The attributes of this phenomenon are discussed.

Copper-induced LDL peroxidation investigated by 1H-NMR spectroscopy

Oxidatively modified LDL (oLDL) is thought to play a key role in the pathogenesis of atherosclerosis. We have studied Cu 2+-induced peroxidation reactions of LDL and have elucidated the sequence of events which subsequently occur within LDL particles by 1H-NMR spectroscopy. Studies of chloroform/methanol extracts show that LDL arachidonate is oxidised by Cu 2+ at a higher rate and to a greater extent than linoleate, giving isomeric hydroperoxides with predominantly trans,trans double-bonds, whilst only cis,trans isomers were detected as intrinsic hydroperoxides in control LDL samples. These intrinsic hydroperoxides were not degraded during peroxidation, suggesting that they are not involved in the initiation of Cu 2+-induced peroxidation. Aldehydes arising from the decomposition of hydroperoxides were also detected, as well as saturated fatty acids which were released into the external aqueous medium. Decomposition pathways of the two major isomeric hydroperoxides are discussed. Cu 2+-induced oxidation of LDL cholesterol appears to occur only after hydroperoxide breakdown, with esterified cholesterol being oxidised to a greater extent than free cholesterol. Phospholipid hydrolysis appeared to parallel the peroxidation of arachidonic acid, and the released lysophosphatidylcholine may become associated with apoB. These results suggest that hydroperoxide breakdown (probably in phospholipids) may be a key event in the peroxidation process, leading to the oxidation of cholesterol and propagation into the core of LDL.

Effects of Gemfibrozil on Low-Density Lipoprotein Particle Size, Density Distribution, and Composition in Patients With Type II Diabetes

To study the effects of gemfibrozil treatment on LDL particle size, density distribution, and composition in NIDDM patients. We performed LDL analyses on 16 NIDDM patients with stable glycemic control. They were randomly allocated to receive either gemfibrozil (n = 8) or a placebo (n = 8) for 3 mo in a double-blind study. The LDL particle size distribution and the particle diameter of the major LDL peak were measured with nondenaturing polyacrylamide gradient gel electrophoresis. The density distribution and composition of LDL were determined with the density gradient ultracentrifugation method. In the gemfibrozil group the mean serum TG concentration decreased by 38%, HDL cholesterol concentration increased by 10%, and LDL cholesterol concentration by 17% (P < 0.05). During gemfibrozil therapy the mean particle diameter of the major LDL peak increased from 244 to 251 A (P < 0.05), whereas in the placebo group the mean LDL particle diameter remained unchanged. We found an inverse correlation between the changes of serum TG and the particle diameters of the major LDL peak (r = 0.85, P < 0.01). Gemfibrozil produced a shift in the LDL density distribution toward lower density. The mean peak density decreased from 1.0371 to 1.0345 g/ml because of a significant rise in the light LDL concentration from 141.0 to 183.2 mg/dl (P < 0.05), whereas the concentration of dense LDL had a tendency to decrease. In the placebo group the LDL density distribution did not change. Gemfibrozil increased the CE-to-TG ratio in LDL core lipids by 27% (P < 0.05); otherwise, the LDL composition was only slightly affected. The results indicate gemfibrozil-induced changes in LDL properties in NIDDM patients are similar to those previously reported in nondiabetic individuals and are related to changes in serum TG level.

Modification of low density lipoprotein by lipoprotein lipase or hepatic lipase induces enhanced uptake and cholesterol accumulation in cells.

Incubation of low density lipoprotein(s) (LDL) with either lipoprotein lipase or hepatic lipase led to modification of the core lipid composition of LDL. Both lipases modified LDL by substantially reducing core triglyceride content without producing marked differences in size, charge, or lipid peroxide content in comparison to native LDL. The triglyceride-depleted forms of LDL that result from treatment with these two enzymes were degraded at approximately twice the rate of native LDL by human monocyte-derived macrophages (HMDM). Lipase-modified LDL degradation was inhibited by chloroquine, suggesting lysosomal involvement in LDL cellular processing. The increased degradation by macrophages of the LDL modified by these lipases was accompanied by enhanced cholesterol esterification rates, as well as by an increase in cellular free and esterified cholesterol content. In a patient with hepatic triglyceride lipase deficiency, degradation of the triglyceride-rich LDL by HMDM was approximately half that of normal LDL. Following in vitro incubation of LDL from this patient with either lipoprotein or hepatic lipase, lipoprotein degradation increased to normal. Several lines of evidence indicate that LDL modified by both lipases were taken up by the LDL receptor and not by the scavenger receptor. 1) The degradation of lipase-modified LDL in nonphagocytic cells (human skin fibroblast and arterial smooth muscle cells) as well as in phagocytic cells (HMDM, J-774, HL-60, and U-937 cell lines) could be dissociated from that of acetylated LDL and was always higher than that of native LDL. A similar pattern was found for cellular cholesterol esterification and cholesterol mass. 2) LDL receptor-negative fibroblasts did not degrade lipase-modified LDL. 3) A monoclonal antibody to the LDL receptor inhibited macrophage degradation of the lipase-modified LDL. 4) Excess amounts of unlabeled LDL competed substantially with 125I-labeled lipase-modified LDL for degradation by both macrophages and fibroblasts. Thus, lipase-modified LDL can cause significant cholesterol accumulation in macrophages even though it is taken up by LDL and not by the scavenger receptor. This effect could possibly be related to the reduced triglyceride content in the core of LDL, which may alter presentation of the LDL receptor-binding domain of apolipoprotein B on the particle surface, thereby leading to increased recognition and cellular uptake via the LDL receptor pathway.

6 Enzymes involved in plasma cholesterol transport

Regulation of plasma cholesterol transport is to a large extent a function of factors that regulate plasma cholesterol esterification and the transfers of cholesteryl esters between plasma lipoprotein fractions. Plasma cholesterol esterification is catalysed by the action of lecithin: cholesterol acyltransferase on lipids on the surface of HDL, while the transfers of cholesteryl esters require activity of a specific lipid transfer protein. Esterification of the cholesterol on the surface of HDL generates a concentration gradient down which unesterified cholesterol moves from tissues into the plasma. Once within the plasma and esterified, the newly formed cholesteryl esters are incorporated initially into the core of HDL particles before being redistributed to other classes of lipoproteins. The end result of these processes of esterification and transfer is that most of the cholesterol in human plasma is accommodated within the core of LDL, where its transport is a function of the highly regulated uptake by tissues of intact LDL particles. The capacity of HDL to act as substrates for lecithin: cholesterol acyltransferase varies inversely with HDL particle size. Thus, factors such as the concentration of triglyceride-rich lipoproteins and activities of the lipid transfer protein, hepatic lipase, lipoprotein lipase and the HDL conversion protein, which are known to influence HDL particle size, may also be important as regulators of plasma cholesterol esterification.

The catabolism of very low density lipoproteins.

The lipolysis of very low density lipoproteins (VLDL) in vitro is a useful model for the study of the process of conversion of this triacylglycerol rich lipoprotein into low (LDL) and high (HDL) density lipoproteins. Data is reviewed to show that a portion of surface cholesterol and phospholipid which becomes redundant during lipolysis is lost from the lipoprotein. In the absence of HDL, the material forms lipoprotein-X (LpX) like vesicles which are not readily disrupted by HDL once they are formed. In the presence of HDL during lipolysis, the material is largely incorporated into HDL. The data is used to suggest a mechanism of formation of LpX-like vesicles in conditions where the production of surface remnants exceeds the capacity of HDL to disrupt them. Evidence is also provided to show that apolipoproteins (apo) C-II, C-III, and E are lost from VLDL and that this loss is primarily in association with a neutral core particle of HDL size which can subsequently exchange lipids and apolipoproteins with plasma HDL. Such a mechanism could account for the removal of apo E and excess cholesteryl ester which is necessary for conversion of VLDL to LDL. The role of hepatic lipase in this process remains speculative. Recent evidence is reviewed and used to propose that the enzyme may serve to rearrange the neutral core and surface composition of LDL and HDL subfractions to allow for the packaging of cholesteryl esters and the cycling of apolipoproteins.

実験的心筋壊死におけるコエンザイムQ&lt;sub&gt;9&lt;/sub&gt;およびビタミンEの検討

In order to elucidate the metabolism of coenzyme Q and vitamin E as the antioxidative agents in the acute vascular accidents, experimental myocardial necrosis induced by isoproterenol injection to rats, was made by the method of Rona. Coenzyme Q9 (Co Q9) and vitamin E (α-tocopherol) in the serum and the lipoprotein fraction were measured. In ordinary state, most of Co Q9 was distributed in VLDL and LDL, and α-tocopherol was in HDL. Co Q9 in VLDL decreased at 6 and 12 hours, most significantly at 12 hours, and in LDL significantly elevated at 12 hours after isoproterenol injection, α-tocopherol in the serum and VLDL showed a rapid decrease, reaching its minimum at 6 hours, and in LDL increased at 12 hours. These results suggest that Co Q9 may locate in the core of VLDL and LDL, and α-tocopherol may predominantly exist in the surface area of the lipoprotein structure.