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1.
Oral nicotine impairs clearance of plasma low density lipoproteins   总被引:1,自引:0,他引:1  
The effect of chronic oral nicotine intake on plasma low density lipoprotein (LDL) clearance, lipid transfer protein, and lecithin:cholesterol acyltransferase (LCAT) was examined in male atherosclerosis susceptible squirrel monkeys. Eighteen yearling primates were divided into two groups: 1) Controls fed isocaloric liquid diet; and 2) Nicotine monkeys given liquid diet supplemented with nicotine at 6 mg/kg body wt/day for a two-year period. Averaged over 24 months of treatment, animals in the Nicotine group had significantly higher levels of plasma and LDL cholesterol compared to Controls while plasma LCAT activity was similar for both groups. Following simultaneous injection of 3H LDL and 14C high density lipoprotein (HDL) cholesteryl ester (CE), removal of the latter was not altered by oral nicotine while plasma clearance of 3H LDL was dramatically delayed in Nicotine monkeys. Transfer of 14C HDL CE to very low density lipoprotein (VLDL)-LDL particles was greatly accelerated in the Nicotine group vs Controls while the reciprocal movement of 3H LDL CE to HDL was only higher in experimental animals at two time points following injection of the isotopes. Results from this study provide evidence that one major detrimental effect of long-term oral nicotine use is an increase in the circulating pool of atherogenic LDL which is due to: 1) accelerated transfer of lipid from HDL; and 2) impaired clearance of LDL from the plasma compartment. Diminished removal of LDL is of particular importance because an extended residence time of these particles in circulation would increase the likelihood of their deposition in the arterial wall.  相似文献   

2.
Free cholesterol is a potent regulator of lipid transfer protein function   总被引:6,自引:0,他引:6  
This study investigates the effect of altered lipoprotein free cholesterol (FC) content on the transfer of cholesteryl ester (CE) and triglyceride (TG) from very low- (VLDL), low- (LDL), and high-(HDL) density lipoproteins by the plasma-derived lipid transfer protein (LTP). The FC content of VLDL and HDL was selectively altered by incubating these lipoproteins with FC/phospholipid dispersions of varying composition. FC-modified lipoproteins were then equilibrated with [3H] TG, [14C]CE-labeled lipoproteins of another class to facilitate the subsequent modification of the radiolabeled donor lipoproteins. LTP was added and the extent of radiolabeled TG and CE transfer determined after 1 h. With either LDL or VLDL as lipid donor, an increase in the FC content of these lipoproteins caused a concentration-dependent inhibition (up to 50%) of CE transfer from these particles, without any significant effect on TG transfer. In contrast, with HDL as donor, increasing the HDL FC content had little effect on CE transfer from HDL, but markedly stimulated (up to 2.5-fold) the transfer of TG. This differential effect of FC on the unidirectional transfer of radiolabeled lipids from VLDL and HDL led to marked effects on LTP-facilitated net mass transfer of lipids. During long-term incubation of a constant amount of LTP with FC-modified VLDL and HDL, the extent of net mass transfer was linearly related to lipoprotein FC content; a 4-fold increase in FC content resulted in a 3-fold stimulation of the CE mass transferred to VLDL, which was coupled to an equimolar, reciprocal transfer of TG mass to HDL. Since lipid transfer between lipoproteins is integral to the process of reverse cholesterol transport, we conclude that lipoprotein FC levels are a potent, positive regulator of the pathways involved in sterol clearance. FC may modulate lipid transfer by altering the availability of CE and TG to LTP at the lipoprotein surface.  相似文献   

3.
Enzymatic and lipid transfer reactions involved in reverse cholesterol transport were studied in healthy and lecithin:cholesterol acyltransferase (LCAT), deficient subjects. Fasting plasma samples obtained from each individual were labeled with [3H]cholesterol and subsequently fractionated by gel chromatography. The radioactivity patterns obtained corresponded to the elution volumes of the three major ultracentrifugally isolated lipoprotein classes (very low density lipoproteins (VLDL), low density lipoproteins (LDL), and high density lipoproteins (HDL)). In healthy subjects, the LCAT activity was consistently found in association with the higher molecular weight portion of HDL. Similar observations were made when exogenous purified LCAT was added to the LCAT-deficient plasma prior to chromatography. Incubation of the plasma samples at 37 degrees C resulted in significant reduction of unesterified cholesterol (FC) and an increase in esterified cholesterol (CE). Comparison of the data of FC and CE mass measurements of the lipoprotein fractions from normal and LCAT-deficient plasma indicates that: (i) In normal plasma, most of the FC for the LCAT reaction originates from LDL even when large amounts of FC are available from VLDL. (ii) The LCAT reaction takes place on the surface of HDL. (iii) The product of the LCAT reaction (CE) may be transferred to either VLDL or LDL although VLDL appears to be the preferred acceptor when present in sufficient amounts. (iv) CE transfer from HDL to lower density lipoproteins is at least partially impaired in LCAT-deficient patients. Additional studies using triglyceride-rich lipoproteins indicated that neither the capacity to accept CE from HDL nor the lower CE transfer activity were responsible for the decreased amount of CE transferred to VLDL and chylomicrons in LCAT-deficient plasma.  相似文献   

4.
Male rats were fed a cholesterol-free diet or the same diet supplemented with either 0.05, 0.1, 0.25, 0.5, 1, or 2% C for 21 days to investigate the effects of cholesterol on secretion of very low density lipoprotein (VLDL). Cholesterol feeding increased plasma and hepatic concentrations of triglyceride (TG) and cholesteryl esters (CE) in a dose-dependent manner. Plasma VLDL and low density lipoprotein (LDL) lipids were elevated by cholesterol feeding, while the high density lipoprotein (HDL) lipids were reduced. The secretion of the VLDL by perfused livers from these cholesterol-fed rats was examined to establish the relationship between the accumulation of lipids in the liver and the concurrent hyperlipemia. Liver perfusions were carried out for 4 h with a medium containing bovine serum albumin (3% w/v), glucose (0.1% w/v), bovine erythrocytes (30% v/v), and a 10-mCi 3H2O initial pulse. Oleic acid was infused to maintain a concentration of 0.6 mM. Hepatic secretion of VLDL-TG, PL (phospholipid), free cholesterol (FC), and CE increased in proportion to dietary cholesterol and was maximal at 0.5% cholesterol in these experiments in which TG synthesis was stimulated by oleic acid. Secretion of VLDL protein and apoB by the perfused liver was also increased. The molar ratios of surface (sum of PL and cholesterol) to core (sum of TG and CE) lipid components of the secreted VLDL, regardless of cholesterol feeding, were the same, as were the mean diameters of the secreted particles. The molar ratios of surface to core lipid of VLDL isolated from the plasma also were not affected by cholesterol feeding. During perfusion with oleic acid of livers from the rats fed the higher levels of cholesterol, the hepatic concentration of CE decreased, while the level of TG was not changed. We conclude that the hypercholesterolemia and hypertriglyceridemia that occur in vivo from cholesterol feeding, concurrent with accumulation of CE and TG in the liver, must result, in part, from increased hepatic secretion of all VLDL lipids and apoB. The VLDL particles produced by the liver of the cholesterol-fed rat are assembled without modification of the surface lipid ratios (PL/FC), but contain a greater proportion of cholesteryl esters compared to triglyceride in the core, because of the stimulated transport of CE from the expanded pool in the liver.(ABSTRACT TRUNCATED AT 400 WORDS)  相似文献   

5.
Six mouse monoclonal antibodies against rabbit apolipoprotein E (apo E) have been developed. Of these monoclonal antibodies, clone 5 revealed a high affinity for purified apo E, very low density lipoprotein (VLDL) and beta-VLDL. This monoclonal antibody was used to prepare an immunoaffinity column. Coupled to Sepharose 4B, this antibody allowed complete removal of lipoproteins containing apo E from plasma of New Zealand white (NZW) rabbits; 62, 46, 14, and 3% of VLDL-, IDL-, LDL-, and HDL-protein, respectively, were bound to the anti-apo E affinity column. The bound VLDL was significantly rich in free cholesterol (FC) and cholesteryl esters (CE) relative to the unbound VLDL, whereas bound IDL, LDL and HDL were significantly rich in FC only. All of the bound fractions were characterized by significantly increased ratios of FC/phospholipids (PL). These results indicate that the two lipoprotein populations with and without apo E have different lipid compositions. The relatively high content of cholesterol in lipoproteins containing apo E suggests a contribution of apo E to plasma cholesterol transport.  相似文献   

6.
Male squirrel monkeys fed ethanol (ETOH) at variable doses were used to determine whether alcohol modifies levels of plasma low density lipoproteins (LDL) in addition to increasing high density lipoproteins (HDL). Because we earlier showed that high alcohol consumption enhances lipoprotein cholesterol synthesis, experiments were also performed to further assess whether ETOH alters lipoprotein clearance and plasma transfer processes in vivo. Monkeys were divided into three groups: Controls fed isocaloric liquid diet; and Low and High ETOH animals fed liquid diet with vodka substituted isocalorically for carbohydrate at 12 and 24 of the calories, respectively. High ETOH primates had significantly more LDL lipid and protein while serum glutamate oxaloacetate transaminase was similar for the three groups. Although removal of 3H LDL cholesteryl ester (CE) from the plasma compartment was not affected by dietary ETOH, transfer of LDL CE to HDL was impaired in the High ETOH group suggesting a mechanism for the enlarged circulating pool of LDL. Transfer of 14C HDL CE to lower density lipoproteins was similar for the three groups. However, ETOH at both doses delayed clearance of radiolabeled HDL CE from circulation. Thus besides enhancing synthesis of lipoproteins, ETOH at a moderately high dose (24% of calories) influences lipoprotein levels in primates by modifying lipid transfer processes (LDL) as well as by altering clearance (HDL) without adversely affecting liver function.  相似文献   

7.
We have investigated the transfer of [14C]cholesterol from labeled bovine heart mitochondria and Friend erythroleukemic cells to high density lipoprotein (HDL), low density lipoprotein (LDL), and very low density lipoprotein (VLDL) fractions from human and rat plasma. The lipoprotein fractions were obtained by molecular sieve chromatography of plasma on agarose A-5m columns. For either membrane system, the highest rate of [14C]cholesterol transfer was observed with the human and the rat HDL fraction. Since the mitochondria lack the receptors for HDL, one may conclude that the observed preferential transfer is not governed by a receptor-controlled interaction of HDL with the membrane. Under conditions where the pool of free cholesterol in the lipoprotein fractions was the same, HDL was a much more efficient acceptor of [14C]cholesterol from mitochondria than LDL or VLDL. Similarly, transfer of [14C]cholesterol proceeded at a higher rate to HDL than to sonicated egg phosphatidylcholine (PC) vesicles, even under conditions where there was a tenfold excess of the vesicle-PC pool over the HDL phospholipid pool. This preferred transfer of [14C]cholesterol to HDL cannot be explained by a random diffusion of monomer cholesterol molecules. Rather, it shows that HDL has a specific effect on this process in the sense that it most likely enhances the efflux of cholesterol from the membrane. Treatment of HDL with trypsin reduced the rate of [14C]cholesterol transfer by 40-50%, indicating that protein component(s) are involved. One of these components appears to be apoA-I, as this protein was shown to enhance the transfer of [14C]cholesterol from mitochondria to lipid vesicles.  相似文献   

8.
Lipid classes and their fatty acids were studied in the major lipoprotein fractions from canine, in comparison with human, plasma. In dogs, high-density-lipoprotein (HDL), the main carrier of plasma phospholipid (PL), cholesterol ester (CE) and free cholesterol, was the most abundant lipoprotein, followed by low and very-low density lipoproteins (LDL and VLDL). Notably, LDL and VLDL contributed similarly to the total dog plasma triacylglycerol (TG). The PL composition was similar in all three lipoproteins, dominated by phosphatidylcholine (PC). Even though the content and composition of lipids within and among lipoproteins differed markedly between dog and man, the total amount of circulating lipid was similar. All canine lipoproteins were relatively richer than those from humans in long-chain (C20-C22) n-6 and n-3 polyunsaturated fatty acids (PUFA) but had comparable proportions of total saturated and monoenoic fatty acids, with 18:2n-6 being the main PUFA in both mammals. The fatty acid profile of canine and human lipoproteins differed because they had distinct proportions of their major lipids. There were more n-3 and n-6 long-chain PUFA in canine than in human plasma, because dogs had more HDL, their HDL had more PC and CE, and both these lipids were richer in such PUFA.  相似文献   

9.
The effects of intravenous injection of lipopolysaccharide (LPS) and tumor necrosis factor alpha (TNF) were investigated in cynomolgus monkeys (Macaca fascicularis). Injection of 20 micrograms/kg of LPS from E. coli (serotype 055:B5) into cynomolgus monkeys fed a monkey chow diet caused a twofold increase in plasma triglyceride and a 25% reduction in plasma cholesterol 48 h after injection. Similar results were found with injection of recombinant human TNF at a dose of 20 micrograms/kg into chow-fed animals. However, injection of the same dose of LPS or TNF into animals fed an atherogenic diet containing saturated fat and cholesterol resulted in a 2.4- to 5-fold increase in plasma triglyceride concentrations and no significant change in plasma cholesterol levels. The fall in plasma cholesterol levels observed in chow-fed animals was associated with a 57% decrease in the cholesteryl ester (CE) content in low density lipoprotein (LDL) and 35% decrease in CE in high density lipoprotein (HDL) in LPS-injected animals, and a decrease of 33% in CE concentration of LDL and 41% in CE of HDL in animals injected with TNF. In animals fed the atherogenic diet containing saturated fat and cholesterol, the injection of both LPS and TNF also resulted in a significant decrease in the CE content of LDL and HDL. However, the plasma total cholesterol levels did not change in the animals fed saturated fat and cholesterol because the decrease in CE content of LDL and HDL was offset by an increase in very low density lipoprotein (VLDL)-CE.(ABSTRACT TRUNCATED AT 250 WORDS)  相似文献   

10.
The clearance of free cholesterol from plasma lipoproteins by tissues is of major quantitative importance, but it is not known whether this is passive or receptor-mediated. Based on our finding that scavenger receptor BI (SR-BI) promotes free cholesterol (FC) exchange between high density lipoprotein (HDL) and cells, we tested whether SR-BI would effect FC movement in vivo using [(14)C]FC- and [(3)H]cholesteryl ester (CE)-labeled HDL in mice with increased (SR-BI transgenic (Tg)) or decreased (SR-BI attenuated (att)) hepatic SR-BI expression. The initial clearance of HDL FC was increased in SR-BI Tg mice by 72% and decreased in SR-BI att mice by 53%, but was unchanged in apoA-I knockout mice compared with wild-type mice. Transfer of FC to non-HDL and esterification of FC were minor and could not explain differences. The hepatic uptake of FC was increased in SR-BI Tg mice by 34% and decreased in SR-BI att mice by 22%. CE clearance and uptake gave similar results, but with much slower rates. The uptake of HDL FC and CE by SR-BI Tg primary hepatocytes was increased by 2.2- and 2.6-fold (1-h incubation), respectively, compared with control hepatocytes. In SR-BI Tg mice, the initial biliary secretion of [(14)C]FC was markedly increased, whereas increased [(3)H]FC appeared after a slight delay. Thus, in the mouse, a major portion of the clearance of HDL FC from plasma is mediated by SR-BI.  相似文献   

11.
Apolipoprotein A-I was purified from human high density lipoprotein and complexed with polyunsaturated phosphatidylcholine (PC) in deoxycholate (Lipostabil); the bile salt was removed subsequently by dialysis. The behavior of the resultant apoA-I/PC complexes was compared with that of Lipostabil in vitro and after injection into rabbits. In vivo apoA-I/PC complexes had the density of HDL throughout but had both alpha and pre beta electrophoretic mobility, the latter probably reflecting dissociation of apoA-I from PC. Lipostabil initially behaved like LDL but gradually acquired the density of HDL after incubation with plasma and in vivo. Both preparations increased plasma total phospholipids in normolipidemic rabbits to a similar extent, but, increments in HDL phospholipid were greater after apoA-I/PC complexes were injected. ApoHDL/PC complexes, prepared in a similar manner, appeared to promote efflux of cholesterol from perfused rabbit aortas in the presence of lecithin:cholesterol acyltransferase (LCAT) activity, consistent with a stimulatory effect on cholesterol mobilization. Injection of apoHDL/PC complexes into hyperlipidemic rabbits decreased plasma cholesterol but increased HDL cholesterol, whereas Lipostabil decreased both. These findings suggest that human apoA-I/PC complexes resemble HDL in their behavior more closely than does Lipostabil, and show that both types of liposome undergo modification upon interaction with plasma. It remains to be shown whether they possess any therapeutic potential.  相似文献   

12.
Administration of phosphatidylinositol (PI) to New Zealand White rabbits increases HDL negative charge and stimulates reverse cholesterol transport. Intravenously administered PI (10 mg/kg) associated almost exclusively with the HDL fraction in rabbits. PI promoted an increase in the hepatic uptake of plasma free cholesterol (FC) and a 21-fold increase in the biliary secretion of plasma-derived cholesterol. PI also increased cholesterol excretion into the feces by 2.5-fold. PI directly affects cellular cholesterol metabolism. In cholesterol-loaded macrophages, PI stimulated cholesterol mass efflux to lipid-poor reconstituted HDL. PI was about half as effective as cAMP at stimulating efflux, and the effects of cAMP and PI were additive. In cultured HepG2 cells, PI-enriched HDL also enhanced FC uptake from HDL by 3-fold and decreased cellular cholesterol synthesis and esterification. PI enrichment had no effect on the selective uptake of cholesterol esters or on the internalization of HDL particles. PI-dependent metabolic events were efficiently blocked by inhibitors of protein kinase C and the inositol signaling cascade.The data suggest that HDL-PI acts via cell surface ATP binding cassette transporters and signaling pathways to regulate both cellular and intravascular cholesterol homeostasis.  相似文献   

13.
Administration of alpha-naphthylisothiocyanate (ANIT) to rats induces changes to plasma lipids consistent with cholestasis. We have previously shown (J. Lipid Res. 37 (1996) 1086) that animals treated with ANIT accumulate large amounts of free cholesterol (FC) and phospholipid (PL)-rich cholestatic lipoproteins in the LDL density range by 48 h. This lipid was cleared by 120 h through apparent movement into HDL with concomitant cholesteryl ester (CE) production. It was hypothesised that the clearance was mediated through the movement of the PL and FC into apolipoprotein A-I (apo A-I) containing lipoproteins followed by LCAT esterification to form CE. To test this hypothesis, rats overexpressing various amounts of human apo A-I (TgR[HuAI] rats) were treated with ANIT (100 mg/kg) and the effect of plasma apo A-I concentration on plasma lipids and lipoprotein distribution was examined. In untreated TgR[HuAI] rats, human apo A-I levels were strongly correlated to plasma PL (r(2)=0. 94), FC (r(2)=0.93) and CE (r(2)=0.90), whereas in ANIT-treated TgR[HuAI] rats, human apo A-I levels were most strongly correlated to CE levels (r(2)=0.80) and an increased CE/FC ratio (r(2)=0.62) and the movement of cholestatic lipid in the LDL to HDL. Since LCAT activity was not affected by ANIT treatment, these results demonstrate that the ability of LCAT to esterify the plasma FC present in cholestatic liver disease is limited by in vivo apo A-I activation of the cholestatic lipid and not by the catalytic capacity of LCAT.  相似文献   

14.
Hyperlipidemia is a prominent feature of the nephrotic syndrome. Lipoprotein abnormalities include increased very low and low density lipoprotein (VLDL and LDL) cholesterol and variable reductions in high density lipoprotein (HDL) cholesterol. We hypothesized that plasma cholesteryl ester transfer protein (CETP), which influences the distribution of cholesteryl esters among the lipoproteins, might contribute to lipoprotein abnormalities in nephrotic syndrome. Plasma CETP, apolipoprotein and lipoprotein concentrations were measured in 14 consecutive untreated and 7 treated nephrotic patients, 5 patients with primary hypertriglyceridemia, and 18 normolipidemic controls. Patients with nephrotic syndrome displayed increased plasma concentrations of apoB, VLDL, and LDL cholesterol. The VLDL was enriched with cholesteryl ester (CE), shown by a CE/triglyceride (TG) ratio approximately twice that in normolipidemic or hypertriglyceridemic controls (P < 0.001). Plasma CETP concentration was increased in patients with untreated nephrotic syndrome compared to controls (3.6 vs. 2.3 mg/l, P < 0.001), and was positively correlated with the CE concentration in VLDL (r = 0.69, P = 0.004) and with plasma apoB concentration (r = 0.68, P = 0.007). Treatment with corticosteroids resulted in normalization of plasma CETP and of the CE/TG ratio in VLDL. An inverse correlation between plasma CETP and HDL cholesterol was observed in hypertriglyceridemic nephrotic syndrome patients (r = -0.67, P = 0.03). The dyslipidemia of nephrotic syndrome includes increased levels of apoB-lipoproteins and VLDL that are unusually enriched in CE and likely to be atherogenic. Increased plasma CETP probably plays a significant role in the enrichment of VLDL with CE, and may also contribute to increased concentrations of apoB-lipoproteins and decreased HDL cholesterol in some patients.  相似文献   

15.
Scavenger receptor BI (SR-BI) mediates the selective uptake of high-density lipoprotein (HDL) cholesteryl ester (CE), a process by which HDL CE is taken into the cell without degradation of the HDL particle. In addition, SR-BI stimulates the bi-directional flux of free cholesterol (FC) between cells and lipoproteins, an activity that may be responsible for net cholesterol efflux from peripheral cells as well as the rapid hepatic clearance of FC from plasma HDL. SR-BI also increases cellular cholesterol mass and alters cholesterol distribution in plasma membrane domains as judged by the enhanced sensitivity of membrane cholesterol to extracellular cholesterol oxidase. In contrast, CD36, a closely related class B scavenger receptor, has none of these activities despite binding HDL with high affinity. In the present study, analyses of chimeric SR-BI/CD36 receptors and domain-deleted SR-BI have been used to test the various domains of SR-BI for functional activities related to HDL CE selective uptake, bi-directional FC flux, and the alteration of membrane cholesterol mass and distribution. The results show that each of these activities localizes to the extracellular domain of SR-BI. The N-terminal cytoplasmic tail and transmembrane domains appear to play no role in these activities other than targeting the receptor to the plasma membrane. The C-terminal tail of SR-BI is dispensable for activity as well for targeting to the plasma membrane. Thus, multiple distinct functional activities are localized to the SR-BI extracellular domain.  相似文献   

16.
The effect of lipoprotein electrostatic properties on the catalytic regulation of hepatic lipase (HL) was investigated. Enrichment of serum or very low density lipoprotein (VLDL) with oleic acid increased lipoprotein negative charge and stimulated lipid hydrolysis by HL. Similarly, enrichment of serum or isolated lipoproteins with the anionic phospholipids phosphatidylinositol (PI), phosphatidic acid, or phosphatidylserine also increased lipoprotein negative charge and stimulated hydrolysis by HL. Anionic lipids had a small effect on phospholipid hydrolysis, but significantly stimulated triacylglyceride (TG) hydrolysis. High density lipoprotein (HDL) charge appears to have a specific effect on lipolysis. Enrichment of HDL with PI significantly stimulated VLDL-TG hydrolysis by HL. To determine whether HDL charge affects the association of HL with HDL and VLDL, HL-lipoprotein interactions were probed immunochemically. Under normal circumstances, HL associates with HDL particles, and only small amounts bind to VLDL. PI enrichment of HDL blocked the binding of HL with HDL. These data indicate that increasing the negative charge of HDL stimulates VLDL-TG hydrolysis by reducing the association of HL with HDL. Therefore, HDL controls the hydrolysis of VLDL by affecting the interlipoprotein association of HL. Lipoprotein electrostatic properties regulate lipase association and are an important regulator of the binding and activity of lipolytic enzymes.  相似文献   

17.
We examined whether postprandial (PP) chylomicrons (CMs) can serve as vehicles for transporting cholesterol from endogenous cholesterol-rich lipoprotein (LDL+HDL) fractions and cell membranes to the liver via lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities. During incubation of fresh fasting and PP plasma containing [(3)H]cholesteryl ester (CE)-labeled LDL+HDL, both CMs and VLDL served as acceptors of [(3)H]CE or cholesterol from LDL+HDL. The presence of CMs in PP plasma suppressed the ability of VLDL to accept [(3)H]CE from LDL+HDL. In reconstituted plasma containing an equivalent amount of triglycerides from isolated VLDL or CMs, a CM particle was about 40 times more potent than a VLDL particle in accepting [(3)H]CE or cholesterol from LDL+HDLs. When incubated with red blood cells (RBCs) as a source for cell membrane cholesterol, the cholesterol content of CMs, VLDL, LDL, and HDL in PP plasma increased by 485%, 74%, 13%, and 30%, respectively, via LCAT and CETP activities. The presence of CMs in plasma suppressed the ability of endogenous lipoproteins to accept cholesterol from RBCs. Our data suggest that PP CMs may play an important role in promoting reverse cholesterol transport in vivo by serving as the preferred ultimate vehicle for transporting cholesterol released from cell membranes to the liver via LCAT and CETP.  相似文献   

18.
Scavenger receptor class B, type I (SR-BI) shows a variety of effects on cellular cholesterol metabolism, including increased selective uptake of high density lipoprotein (HDL) cholesteryl ester, stimulation of free cholesterol (FC) efflux from cells to HDL and phospholipid vesicles, and changes in the distribution of plasma membrane FC as evidenced by increased susceptibility to exogenous cholesterol oxidase. Previous studies showed that these multiple effects require the extracellular domain of SR-BI, but not the transmembrane and cytoplasmic domains. To test whether 1) the extracellular domain of SR-BI mediates multiple activities by virtue of discrete functional subdomains, or 2) the multiple activities are, in fact, secondary to and driven by changes in cholesterol flux, the extracellular domain of SR-BI was subjected to insertional mutagenesis by strategically placing an epitope tag into nine sites. These experiments identified four classes of mutants with disruptions at different levels of function. Class 4 mutants showed a clear separation of function between HDL binding, HDL cholesteryl ester uptake, and HDL-dependent FC efflux on one hand and FC efflux to small unilamellar vesicles and an increased cholesterol oxidase-sensitive pool of membrane FC on the other. Selective disruption of the latter two functions provides evidence for multiple functional subdomains in the extracellular receptor domain. Furthermore, these findings uncover a difference in the SR-BI-mediated efflux pathways for FC transfer to HDL acceptors versus phospholipid vesicles. The loss of the cholesterol oxidase-sensitive FC pool and FC efflux to small unilamellar vesicle acceptors in Class 4 mutants suggests that these activities may be mechanistically related.  相似文献   

19.
Animals of various species are widely used as models with which to study atherosclerosis and the lipoprotein metabolism. The objective of this study was to investigate the lipoprotein profiles in Wistar rats and New Zealand white rabbits with experimentally induced hyperlipidemia by means of ultracentrifugation. The Schlieren curves were utilized to compare suckling and adult rat sera to determine whether aging causes alterations in lipoprotein profiles. A striking feature of the data is the high concentration of low-density lipoproteins (LDL), (>5.2 mmol/l cholesterol) in the 2-week old rat serum pool which was greatly decreased in the 3-weeks rat serum pool (<1.3 mmol/l cholesterol). Additional experiments were performed to permit a direct comparison of the amounts of lipoprotein present in rat sera in experimental hyperlipidemia post-Triton WR 1339 administration. Rapid changes in concentrations in very low-density lipoproteins (VLDL), LDL and high-density lipoproteins (HDL) were observed after Triton injection. The administration of Triton WR 1339 to fasted rats resulted in an elevation of serum cholesterol levels. Triton physically alters VLDL, rendering them refractive to the action of lipolytic enzymes in the blood and tissues, preventing or delaying their removal from the blood. Whereas the VLDL concentration was increased markedly, those of LDL and HDL were decreased at 20 h after Triton treatment. Rabbits were fed a diet containing 2% cholesterol for 60 days to develop hyperlipidemia and atheromatous aortic plaques. A combination of preparative and analytical ultracentrifugation was used to investigate of LDL aliquots, to prepare radioactive-labeled lipoproteins and to study induced hyperlipidemia in rabbits. Analytical ultracentrifugation was applied to investigate the LDL flotation peaks before and after cholesterol feeding of rabbits. Modified forms of LDL were detected in the plasma of rabbits with experimentally induced atherosclerosis. ApoB-containing particles, migrating as LDL, intermediate density lipoproteins and VLDL were the most abundant lipoproteins. Gamma camera in vivo scintigraphy on rabbits with radiolabeled lipoproteins revealed visible signals corresponding to atherosclerotic plaques of the aorta and carotid arteries.  相似文献   

20.
The effect of dietary restriction (half of the control ration) on VLDL turnover was investigated in cholesterol-fed rabbits. Rabbits on standard, cholesterol and restricted cholesterol diets were injected with homologous 125I-labelled VLDL. Accompanying the amplification of hypercholesterolemia, additional disturbances of VLDL turnover were observed when cholesterol feeding was associated with dietary restriction. Cholesterol-fed rabbits with normal caloric ration exhibited delayed clearance of 125I-labelled apolipoprotein B component of VLDL compared to control rabbits. This was markedly accentuated in underfed rabbits, indicating further down-regulation of apolipoprotein B,E receptors in these animals. Furthermore, a reduced proportion of radiolabelled apolipoprotein B was converted from VLDL to intermediate-density lipoprotein (IDL) and LDL in both groups receiving cholesterol-rich diets. Thus, the combination of further impairment in plasma clearance of VLDL and the poor conversion into IDL and LDL could account for the massive increase of beta-VLDL in underfed animals on cholesterol-rich diets.  相似文献   

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