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PubMed1991

Mechanisms of inhibition by apolipoprotein C of apolipoprotein E-dependent cellular metabolism of human triglyceride-rich lipoproteins through the low density lipoprotein receptor pathway.

The mechanism of inhibition by apolipoprotein C of the uptake and degradation of triglyceride-rich lipoproteins from human plasma via the low density lipoprotein (LDL) receptor pathway was investigated in cultured human skin fibroblasts. Very low density lipoprotein (VLDL) density subfractions and intermediate density lipoprotein (IDL) with or without added exogenous recombinant apolipoprotein E-3 were used. Total and individual (C-I, C-II, C-III-1, and C-III-2) apoC molecules effectively inhibited apoE-3-mediated cell metabolism of the lipoproteins through the LDL receptor, with apoC-I being most effective. When the incubation was carried out with different amounts of exogenous apoE-3 and exogenous apoC, it was shown that the ratio of apoE-3 to apoC determined the uptake and degradation of VLDL. Excess apoE-3 overcame, at least in part, the inhibition by apoC. ApoC, in contrast, did not affect LDL metabolism. Neither apoA-I nor apoA-II, two apoproteins that do not readily associate with VLDL, had any effect on VLDL cell metabolism. The inhibition of VLDL and IDL metabolism cannot be fully explained by interference of association of exogenous apoE-3 with or displacement of endogenous apoE from the lipoproteins. IDL is a lipoprotein that contains both apoB-100 and apoE. By using monoclonal antibodies 4G3 and 1D7, which specifically block cell interaction by apoB-100 and apoE, respectively, it was possible to assess the effects of apoC on either apoprotein. ApoC dramatically depressed the interaction of IDL with the fibroblast receptor through apoE, but had only a moderate effect on apoB-100. The study thus demonstrates that apoC inhibits predominantly the apoE-3-dependent interaction of triglyceride-rich lipoproteins with the LDL receptor in cultured fibroblasts and that the mechanism of inhibition reflects association of apoC with the lipoproteins and specific concentration-dependent effects on apoE-3 at the lipoprotein surface.

Antibodies, Monoclonal↗
PubMed1983

Effect of removal of lipoproteins of different composition on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and hepatic very low density lipoprotein secretion.

The effect of remnant lipoproteins on hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and hepatic very low density lipoprotein (VLDL) secretion was studied in the perfused rat liver and in vivo. As had been observed previously, when the liver was perfused with a lipid-free medium, HMG-CoA reductase activity increased about twofold after 150 min, and this increase could be prevented by the addition of chylomicron remnants to the medium. However, suppression below base line activity did not occur even with increasing amounts of remnant cholesterol. When chylomicron remnants prepared from triglyceride-rich particles were included in the medium, reductase activity was increased even above that in the control perfusions despite the fact that approximately the same amount of cholesterol was removed from these particles as from standard particles. In contrast, particles that were low in triglycerides and rich in cholesterol not only prevented the rise in reductase activity but inhibited it significantly below base line activity. Again, the total amount of cholesterol removed was the same as with the other types of particles. These results suggested that both the triglycerides and cholesterol exerted an effect on HMG-CoA reductase. Consistent with this hypothesis, a significant correlation was found between reductase activity and the ratio of triglycerides to cholesterol removed, but not to either alone. To explore the role of triglycerides further, the effect of these lipoprotein particles on VLDL secretion was determined. VLDL secretion was stimulated by both standard and triglyceride-rich remnants but not by triglyceride-poor remnants. The degree of stimulation with standard chylomicron was comparable to that induced by infusion of a comparable fatty acid load as oleic acid bound to albumin. In vivo a similar effect of these lipoproteins on HMG-CoA reductase activity was observed. Rats were injected with a lipoprotein bolus containing 7 mg of cholesterol, and reductase activity in the liver was measured 2 hr later. Standard chylomicrons and triglyceride-rich chylomicrons stimulated reductase to 157% and 187% of control activity, respectively, whereas cholesterol-rich VLDL suppressed reductase activity to 30% of control activity. These observations support the hypothesis that remnant lipoproteins have a dual effect on hepatic HMG-CoA reductase activity; the cholesterol in these lipoproteins suppresses hepatic reductase activity while the triglycerides concommitantly delivered stimulate reductase activity at least in part because they stimulate hepatic VLDL secretion. Therefore, the net response of hepatic HMG-CoA reductase to a particular dietary lipoprotein will depend upon the balance between the cholesterol and triglycerides carried to the liver.-Van Zuiden, P. E. A., S. K. Erickson, and A. D. Cooper. Effect of removal of lipoproteins of different composition on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and hepatic very low density lipoprotein secretion.

Animals↗
PubMed1984

Effects of probucol on the in vivo plasma clearance of human low density lipoproteins in rabbits and on the expression of lipoprotein receptors in vitro.

The purpose of this study was to investigate the effects of probucol on the plasma levels of low density lipoproteins in rabbits and whether the resulting decrease of low density lipoproteins was related to the effects of probucol on the expression of lipoprotein receptors. Probucol administration effectively lowered plasma cholesterol in normal rabbits. Both low density and high density lipoprotein cholesterol decreased, as well as apo B in the former fraction. Probucol had no effect on the fractional catabolic rate of low density lipoprotein while the flux of this lipoprotein decreased to about 50%. Moreover both the binding of lipoproteins to liver membranes and the in vitro uptake of low density lipoprotein by human skin fibroblasts were not affected by the drug. These findings are consistent with an effect of probucol on low density lipoprotein synthesis.

Animals↗
PubMed1997

Non-specific inhibition by human lipoproteins of endothelium dependent relaxation in rat aorta may be attributed to lipoprotein phospholipids.

OBJECTIVE: In vitro incubation of low-density lipoprotein (LDL) is reported to attenuate endothelium dependent relaxation mediated by acetylcholine (ACh) while not affecting endothelium-independent relaxation. This study was designed to examine the effects of other lipid-carrying lipoproteins as well as to study their effects on responses mediated by endothelium dependent agonists other than ACh. METHODS: The effects of human LDL, very-low-density lipoprotein (VLDL) and high density lipoprotein (HDL) on endothelium-dependent relaxation by ACh, histamine and the calcium ionophore, A23187, and endothelium-independent relaxation by sodium nitroprusside (SNP) were investigated is rat isolated aortic rings. The effects of combined LDL and HDL incubation on responses mediated by ACh were also examined. Control experiments included experiments examining the effects of bovine serum albumin on responses mediated by ACh. Thiobarbituric-acid-reactive substances (TBARS) measured before and after organ bath incubation indicated little oxidation of the lipoproteins used. RESULTS: Maximal responses to ACh were inhibited by LDL, VLDL and HDL (0.02 and 0.2 mg protein/ml), to histamine by LDL (0.2 mg protein/ml), VLDL (0.02 and 0.2 mg protein/ml) and HDL (0.02 mg protein/ml) and to A23187 by LDL (0.2 mg protein/ml). VLDL (0.2 mg protein/ml) and HDL (0.02 and 0.2 mg protein/ml). A small but significant correlation (r = 0.54, P = 0.01) was observed between the level of inhibition of the endothelium-dependent responses and lipoprotein phospholipid concentration in the organ bath but not between the level of inhibition and cholesterol (free and esterified) or triglyceride concentrations. Responses to SNP were unaffected by LDL, VLDL and HDL. Combined incubation of tissues with LDL (0.2 mg protein/ml) and HDL (0.2 mg protein/ml) significantly increased maximal responses to ACh (pre-lipoproteins 81.8 +/- 5.7 vs plus-LDL/HDL 100 +/- 0.0; P < 0.05). Bovine serum albumin had no effect on the maximal responses to ACh. CONCLUSIONS: We conclude that inhibition by human lipoproteins of endothelium-dependent agonists occurs with LDL, HDL and VLDL and suggest that this may be due to the phospholipid content of each lipoprotein. However, combined incubation of HDL with LDL negates this effect and an increased maximal response to ACh is reported.

Acetylcholine↗
PubMed1975

Swine lipoproteins and atherosclerosis. Changes in the plasma lipoproteins and apoproteins induced by cholesterol feeding.

Cholesterol feeding in miniature swine resulted in a hypercholesterolemia with a distinctive hyperlipoproteinemia and the subsequent development of atherosclerosis. Alterations in the type and distribution of plasma lipoproteins induced by cholesterol feeding were as follows: (a) the occurrence of beta-migrating lipoproteins (B-VLDL) as well as very low density lipoproteins in the d less than 1.006 ultracentrifugal fraction; (b) an increased prominence of the intermediate lipoproteins (d = 1.006-1.02); (c) an increased prominence of low density lipoproteins; and (d) the occurrence of a distinctive lipoprotein with alpha mobility which was referred to as HDLc (cholesterol induced). Characterization of the various plasma lipoproteins included chemical composition, size by electron microscopy, and apoprotein content. The B-VLDL resembled the beta-migrating lipoproteins of human Type III hyperlipoproteinemia and contained a prominent protein equivalent to the arginine-rich apoprotein in addition to the B apoprotein, apo-A-I, and the fast-migrating apoproteins (apo-C). The HDLc were rich in cholesterol, ranged in size from 100 to 240 A in diameter, and contained the arginine-rich apoprotein and apo-A0I but lacked the B apoprotein. The arginine-rich apoproteins isolated from B-VLDL and HDLc by gel chromatography were similar in amino acid analyses, with glutamic acid as their amino-terminal residue. The occurrence of a spectrum of cholesterol-rich lipoproteins which contained the arginine-rich apoprotein with the occurrence of accelerated atherosclerosis suggested an interesting, although speculative, association.

Amino Acids↗
PubMed1996

Suppression of diet-induced atherosclerosis in low density lipoprotein receptor knockout mice overexpressing lipoprotein lipase.

Lipoprotein lipase (LPL) is a key enzyme in the hydrolysis of triglyceride-rich lipoproteins. Conflicting results have been reported concerning its role in atherogenesis. To determine the effects of the overexpressed LPL on diet-induced atherosclerosis, we have generated low density lipoprotein receptor (LDLR) knockout mice that overexpressed human LPL transgene (LPL/LDLRKO) and compared their plasma lipoproteins and atherosclerosis with those in nonexpressing LDLR-knockout mice (LDLRKO). On a normal chow diet, LPL/LDLRKO mice showed marked suppression of mean plasma triglyceride levels (32 versus 236 mg/dl) and modest decrease in mean cholesterol levels (300 versus 386 mg/dl) as compared with LDLRKO mice. Larger lipoprotein particles of intermediate density lipoprotein (IDL)/LDL were selectively reduced in LPL/LDLRKO mice. On an atherogenic diet, both mice exhibited severe hypercholesterolemia. But, mean plasma cholesterol levels in LPL/ LDLRKO mice were still suppressed as compared with that in LDLRKO mice (1357 versus 2187 mg/dl). Marked reduction in a larger subfraction of IDL/LDL, which conceivably corresponds to remnant lipoproteins, was observed in the LPL/LDLRKO mice. LDLRKO mice developed severe fatty streak lesions in the aortic sinus after feeding with the atherogenic diet for 8 weeks. In contrast, mean lesion area in the LPL/LDLRKO mice was 18-fold smaller than that in LDLRKO mice. We suggest that the altered lipoprotein profile, in particular the reduced level of remnant lipoproteins, is mainly responsible for the protection by LPL against atherosclerosis.

Animals↗
PubMed2003

Intestinal lipoprotein assembly in apobec-1-/- mice reveals subtle alterations in triglyceride secretion coupled with a shift to larger lipoproteins.

Mammalian enterocytes express apolipoprotein (apo)B-48, which is produced after posttranscriptional RNA editing of the nuclear apoB-100 transcript by the catalytic deaminase apobec-1. Earlier studies in apobec-1-/- mice revealed an apoB-100-only lipoprotein profile but no gross defects in triglyceride absorption. However, subtle defects may have been obscured by the mixed genetic background. In addition, the intrinsic susceptibility to proteolytic degradation of intestinal apoB-100 and apoB-48 has been questioned. Accordingly, we examined triglyceride absorption, intestinal apoB expression, and lipoprotein secretion in apobec-1-/- mice backcrossed into a C57BL/6 background. Inbred apobec-1-/- mice absorb triglyceride normally, yet secrete triglyceride-rich lipoproteins more slowly than wild-type congenic controls. There was comparable induction of apoB synthesis in response to fat feeding in both genotypes, but apoB-100 was preferentially retained and more extensively degraded than apoB-48. By contrast, synthesis, secretion, and content of apo A-IV were indistinguishable in apobec-1-/- and wild-type mice with 100% recovery, suggesting no degradation of this apoprotein in either genotype. Newly secreted lipoproteins from isolated enterocytes of wild-type mice revealed apoB-48 in both high-density lipoproteins and very low-density lipoproteins. By contrast, apobec-1-/- mice secreted apoB-100-containing particles that were almost exclusively in the low and very low-density lipoproteins range with no apoB-100-containing high-density lipoproteins. These studies establish the existence of preferential degradation of intestinal apoB-100 and subtle defects in triglyceride secretion in apobec-1-/- mice, coupled with a shift to the production of larger particles, findings that suggest an important divergence in intestinal lipoprotein assembly pathways with the different isoforms of apoB.

APOBEC-1 Deaminase↗
PubMed1983

Quantification of lipoprotein cholesterol in serum from children with different lipoprotein profiles: heparin-calcium precipitation and ultracentrifugation compared.

We compared the serum lipoprotein cholesterol concentrations in subgroups of children (n = 360), ages 5-17 years, as measured by the heparin-Ca2+ and preparative ultracentrifugation methods. Children were grouped from the total population on the basis of their previous results for serum beta- and pre-beta-lipoprotein cholesterol (Group I: low beta- and low pre-beta-; Group II: high beta- and low pre-beta; Group III: high beta- and high pre-beta-; Group IV: low beta- and high pre-beta-). The values for very-low-density (VLDL) cholesterol by ultracentrifugation method were 44, 53, 15, and 10 mg/L greater than the values for pre-beta-lipoprotein cholesterol by the heparin-Ca2+ method in Groups I, II, III, and IV, respectively; the differences were not significant in Group IV. The values of low-density (LDL) cholesterol were 64, 137, 144, and 73 mg/L less than the values for beta-lipoprotein cholesterol in Groups I, II, III, and IV, respectively (p less than 0.005). On the other hand, high-density (HDL) cholesterol concentrations in the respective four groups were 10, 37, 93, and 52 mg/L greater than alpha-lipoprotein cholesterol concentrations; the differences were significant for Groups II, III, and IV (p less than 0.005). Overall, the values for LDL-cholesterol correlated highly with beta-lipoprotein cholesterol (r = 0.94), whereas correlations for VLDL- and HDL-cholesterol values with pre-beta-lipoprotein cholesterol (r = 0.76) and alpha-lipoprotein cholesterol (r = 0.77) were somewhat lower. The differences between these two methods may result from their different operational definitions for measuring serum lipoproteins and the possibility that without appropriate corrections the values obtained by preparative ultracentrifugation do not serve as reference values.

Adolescent↗
PubMed2000

Influence of baseline values on lipids, lipoproteins and fibrinolytic parameters during treatment of hypertension with cilnidipine.

Sixteen adult hypertensive patients of both sexes, classified as having 'medium' (total lipid profile 240-300 mg dl(-1)), and 'high' (total lipid profile >300 mg dl(-1)) baseline values, underwent serum lipids, lipoproteins and plasma fibrinolytic parameters evaluations after 3 months of cilnidipine treatment. Patients with 'medium baseline values' did not have any change in lipids, lipoproteins and fibrinolytic parameters while patients with 'high baseline values' had beneficial lipid and lipoprotein changes [decreases in total cholesterol (TC), triglycerides (TG), very low density lipoprotein-cholesterol (VLDLC) and increases in high density lipoprotein-cholesterol (HDLC), and HDLC/TC ratio] after cilnidipine treatment. Changes in lipids were negatively associated with fibrinolysis for the patients with 'medium baseline values' and positively associated in patients with 'high baseline values' after cilnidipine treatment. Reduction in blood pressure was related to fibrinolysis and reduced risk of coronary heart disease in the patients with 'high baseline values' after cilnidipine therapy. These results show that during cilnidipine treatment, the baseline lipid profile levels of the patients may influence the lipid altering actions as well as the interaction between lipids and fibrinolysis.

Aged↗
PubMed1994

Triglyceride-rich lipoproteins of subjects heterozygous for apolipoprotein E2(Lys146-->Gln) are inefficiently converted to cholesterol-rich lipoproteins.

The APOE*2(Lys146-->Gln) allele behaves like a dominant trait in the expression of familial dysbetalipoproteinemia (FD) (Smit et al., J. Lipid Res. 1990; 31: 45-53). FD patients carrying the APOE*2(Lys146-->Gln) allele exhibit less elevated cholesterol to triglyceride ratios in the d < 1.019 g/ml lipoprotein density fraction as compared to classical FD patients displaying homozygosity for the APOE*2(Arg158-->Cys) allele (0.8 vs. 1.4). Upon treatment of complete serum with lipoprotein lipase (LPL), the mean cholesterol to triglyceride molar ratio of the d < 1.019 g/ml lipoprotein fraction in these FD patients increased only marginally (from 0.8 to 1.1), as compared with that of classical FD subjects (from 1.4 to 2.6) and non-FD control subjects (from 0.7 to 1.5). In order to obtain further evidence for an inefficient lipolysis of the d < 1.019 g/ml lipoprotein fraction in APOE*2(Lys146-->Gln) carriers, possibly in combination with a less efficient cholesteryl ester transfer protein (CETP) activity, blood samples of APOE*2(Lys146-->Gln) allele carrying FD patients were analysed and compared with classical FD patients and controls. In the APOE*2(Lys149-->Gln) allele carrying FD patients were analysed and compared with classical FD patients and controls. In the APOE*2(Lys146-->Gln) FD patients, the increase in plasma cholesterol was mainly confined to the very low density lipoprotein (VLDL) fraction, whereas in classical FD patients, the levels of cholesterol in the intermediate density lipoprotein (IDL) fraction was also dramatically increased (ratios of VLDL to IDL cholesterol are 4.7 and 2.6, respectively). Family analyses of the APOE*2(Lys146-->Gln) FD subjects showed that the apo E to apo B ratio in the d < 1.019 g/ml lipoprotein fraction of allele carriers is 3.5 times as high as that found in non-carriers (2.8 vs. 0.8, by wt.). Also, in the APOE*2(Lys146-->Gln) allele carrying family members, the ratio of cholesterol to triglyceride of the d < 1.019 g/ml lipoprotein fraction is less markedly elevated upon addition of LPL when compared to that in non-carrying controls (from 1.1 to 1.8 vs 0.7 to 1.6). The efficiency of the d < 1.019 g/ml lipoprotein fraction of APOE*2(Lys146-->Gln) FD patients to compete with low density lipoprotein (LDL) for binding to the LDL receptor is intermediate to that of controls and classical APOE*2(Arg158-->Cys) homozygous FD patients. These findings suggest that in APOE*2(Lys146-->Gln) allele carriers, the conversion of VLDL into IDL is impaired due to an inefficient lipolysis, possibly in combination with a retarded CETP activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1999

Differences in the lipoprotein binding profile of halofantrine in fed and fasted human or beagle plasma are dictated by the respective masses of core apolar lipoprotein lipid.

Halofantrine hydrochloride (Hf) is an orally active, highly lipophilic antimalarial indicated for the treatment of multi-drug resistant Plasmodium falciparum. In this study, we have examined the binding profile of Hf to the various classes of human and beagle plasma lipoproteins as such interactions have been implicated in a post-prandial plasma lipoprotein-induced decrease in the total clearance and volume of distribution of Hf. The distribution of Hf within plasma was dominated by interaction with the various classes of plasma lipoproteins, and the characteristics and extent of binding were markedly different between species and between pre- and post-prandial plasma. In an attempt to understand the basis for the differential binding of Hf to the various lipoprotein fractions, the relationship between the proportion of Hf associated with each lipoprotein fraction (as a function of the respective mass of protein, triglyceride, cholesterol, and phospholipid) was investigated. The data indicated that the distribution of Hf between plasma lipoproteins was highly correlated with the apolar lipid load of individual plasma lipoprotein fractions suggesting that the mechanism of association was primarily via solubilization in the lipoprotein apolar lipid core. These data suggest that acute changes in plasma lipoprotein profiles, such as encountered post-prandially or in disease states such as malaria, will likely have an impact on the plasma lipoprotein binding of Hf.

Animals↗
PubMed1984

Metabolism of apolipoproteins B-48 and B-100 of triglyceride-rich lipoproteins in normal and lipoprotein lipase-deficient humans.

The metabolism of apolipoproteins B-48 and B-100 (apo B-48 and B-100) in large triglyceride-rich lipoproteins (300 to 1500 A in diameter) has been compared in three normal subjects and two subjects with genetically determined deficiency of lipoprotein lipase. The triglyceride-rich lipoproteins were obtained from a lipoprotein lipase-deficient donor 4 hr after a fat-rich meal in order to obtain chylomicrons (containing apo B-48) and very low density lipoproteins (VLDL) (containing apo B-100), whose properties had not been modified by the action of this enzyme. The triglyceride-rich lipoproteins were labeled with 125I and injected intravenously into recipients who had fasted overnight. In normal recipients, most of the apo B-48 was removed from the blood within 15 min, and most of the apo B-100 was removed within 30 min. In the lipoprotein lipase-deficient recipients, most of the injected apo B-100 remained in the blood for more than 8 hr; removal of apo B-48 was only slightly more rapid. In all subjects, only trace amounts of either protein were found in lipoproteins more dense than 1.006 g/ml. The results indicate that (i) the removal of the apo B of both chylomicrons and large VLDL from the blood is dependent upon the hydrolysis of their component triglycerides by lipoprotein lipase, and (ii) little or no apo B-48 of chylomicrons or apo B-100 of large VLDL is converted appreciably to low density lipoproteins (LDL). Our results suggest that the reported variability of the conversion of VLDL to LDL may be related to the size and composition of the particles secreted from the liver. The rapid production of remnant particles that are removed efficiently by the liver may minimize the opportunity for further reactions leading to the formation of LDL.

Apolipoprotein B-100↗
PubMed2003

Impact of sepsis-induced changes in plasma on LPS interactions with monocytes and plasma lipoproteins: roles of soluble CD14, LBP, and acute phase lipoproteins.

Sepsis-induced changes in human plasma decrease LPS association with monocytes by regulating dynamic interactions among LPS, monocytes, and plasma lipoproteins. In the physiological environment of undiluted human serum, we have found that: (i) LPS binds transiently to monocytes and is released into plasma lipoproteins; (ii) the release of LPS from monocytes is dependent upon lipoprotein acceptors and is enhanced by soluble CD14 (sCD14); and (iii) both lipoproteins and sCD14 can attenuate cytokine responses in monocytes that have already bound LPS. Whereas LPS binding protein (LBP) also inhibited LPS responses after LPS had bound to monocytes, this did not require extensive release of cell-bound LPS as was observed with sCD14. In the serum of septic patients, both free LPS and monocyte-bound LPS were usually transferred to lipoproteins at an accelerated rate. In spite of a sharp decline in HDL levels, HDL remained the dominant LPS acceptor in many severely septic patients, whereas in some cases LPS binding shifted largely to a non-HDL lipoprotein fraction that co-eluted according to size with very low-density lipoprotein (VLDL). Preliminary data suggest that these lipoproteins have a very low density, and they contain apolipoprotein E and higher than normal proportions of the total lipoprotein cholesterol, phospholipid, apolipoprotein B, and serum amyloid A. The data suggest that the VLDL fraction contains acute phase lipoproteins of significantly altered composition that can replace HDL as the dominant LPS acceptor during sepsis when HDL levels are low.

Acute-Phase Proteins↗
PubMed2000

Phospholipid transfer protein gene knock-out mice have low high density lipoprotein levels, due to hypercatabolism, and accumulate apoA-IV-rich lamellar lipoproteins.

Phospholipid transfer protein gene knock-out (Pltp KO) mice have defective transfer of very low density lipoprotein (VLDL) phospholipids into high density lipoprotein (HDL) and markedly decreased HDL levels (Jiang et al. 1999. J. Clin. Invest. 103: 907-914). These animals also accumulated VLDL- and LDL-sized lipoproteins on a high saturated fat diet. The goals of this study were to further characterize the abnormal lipoproteins of Pltp KO mice and to determine the mechanisms responsible for low HDL levels. A lipoprotein fraction enriched in lamellar structures was isolated from the low density lipoprotein (LDL) region and was shown to be phospholipid- and free cholesterol-rich and to have apoA-IV (55%) and apoE (25%) as major apolipoproteins. The lamellar lipoproteins accumulating in these mice probably represent surface material derived from triglyceride-rich lipoproteins (TRL). The HDL was found to be protein-rich (primarily apoA-I) and specifically depleted in phosphatidylcholine (PC) (28% in wild-type mice (WT) vs. 15% in Pltp KO mice, P < 0.001). Unexpectedly, turnover studies using autologous HDL revealed a profound 4-fold increase in the catabolism of HDL protein and cholesteryl ester in Pltp KO mice compared to wild-type, with minor differences in synthesis rates. In contrast, injection of WT mouse HDL into Pltp KO mice showed only a 2-fold increase in fractional catabolism. Reminiscent of the defect in Tangier disease, the failure of transfer of PC from TRL into the HDL fraction results in dramatic hypercatabolism of HDL. These results suggest that defective phospholipid transfer from TRL into HDL, arising from decreased lipolysis or decreased PLTP activity, could lead to hypoalphalipoproteinemia characterized by hypercatabolism of HDL protein. lipoprotein levels, due to hypercatabolism, and accumulate apoA-IV-rich lamellar lipoproteins.

Animals↗
PubMed1968

Effect of phospholipase A treatment of low density lipoproteins on the dextran sulfate--lipoprotein interaction.

The effect of phospholipase A on the interaction of low density lipoproteins of the S(f) 0-10 class with dextran sulfate was studied in phosphate buffer of pH 7.4, ionic strength 0.1, by chemical, spectrophotometric, and centrifugal methods. When low density lipoproteins that had been treated with phospholipase A were substituted for untreated lipoproteins, the amount of insoluble dextran sulfate-lipoprotein complex formed was greatly reduced. Hydrolysis of over 20% of the lecithin and phosphatidyl ethanolamine constituents of the lipoproteins prevented the formation of insoluble complex. However, even the lipoproteins in which almost all the phosphoglycerides were hydrolyzed produced soluble complex, which was converted to insoluble complex upon addition of magnesium sulfate. It is apparent that the lipoproteins altered extensively by treatment with phospholipase A retain many characteristic properties of native low density lipoproteins. Fatty acids, but not lysolecithin, released by the action of phospholipase A interfered with the formation of insoluble complex; this interference was due to association of the fatty acids with the lipoproteins. With increases in the concentration of the associated fatty acids, the amounts of magnesium ion required for the conversion of soluble complex to insoluble complex increased progressively. Charge interaction is evidently of paramount importance in the formation of sulfated polysaccharide-lipoprotein complexes.

Animals↗
PubMed1981

Incorporation of phosphatidylcholine into spherical and discoidal lipoproteins during incubation of egg phosphatidylcholine vesicles with isolated high density lipoproteins or with plasma.

Incubation of phosphatidylcholine vesicles with isolated high density lipoproteins (HDL) or with whole plasma results in transfer of phospholipid into HDL. To investigate the mechanisms of this process, small unilamellar vesicles of egg phosphatidylcholine were incubated with human HDL3 (d 1.125 to 1.210 g/ml) or with plasma and were subsequently analyzed by density gradient ultracentrifugation and negative stain electron microscopy. Incubation of vesicles with isolated HDL3 resulted in formation of both discoidal lipoproteins (1.04 to 1.06 g/ml) and phospholipid-enriched spherical lipoproteins (1.10 to 1.14 g/ml). The lipid bilayer discoidal lipoproteins had dimensions approximately 22 X 5.4 nm and contained phospholipid, apoA-I, and apoA-II. The phospholipid-enriched sperical HDL were increased in diameter and decreased in density compared to HDL3. With maximum phospholipid uptake these lipoproteins had a similar density, size, and lipid composition to HDL2a, a phospholipid-rich subfraction of HDL isolated from human plasma between 1.100 to 1.125 g/ml. Scanning microcalorimetry of the phospholipid-enriched HDL showed, compared to HDL3, a decrease in the temperature and enthalpy of lipoprotein denaturation. This altered denaturation pattern was similar to that of plasma HDL2a. Following incubation of vesicles in plasma, there was an increase in phospholipid-rich lipoproteins within the HDL2 density range (1.070 to 1.125 g/ml), and disappearance of lipoproteins from the HDL3 density range (1.125 to 1.210 g/ml). The phospholipid-rich HDL2 contained a major peak (d 1.095 to 1.125 g/ml), which consisted of only spherical particles and a smaller peak (d 1.070 to 1.095 g/ml), which included a population of lipid bilayer discs. Thus, during incubation of vesicles with isolated HDL3, there is insertion of phospholipid into HDL3, producing spherical lipoproteins which have some properties in common with HDL2a. Discoidal lipoproteins are also formed, probably as a result of interaction of vesicles with small amounts of apoA-I and apoA-II released from HDL3. The uptake of phosphatidylcholine by HDL in whole plasma occurs by similar mechanisms.

Calorimetry, Differential Scanning↗
PubMed1994

Regulation of lipid transfer between lipoproteins by an endogenous plasma protein: selective inhibition among lipoprotein classes.

Lipid transfer protein (LTP) remodels plasma lipoproteins by promoting mass transfers of cholesteryl ester (CE) and triglyceride between lipoproteins. We have investigated the capacity of an additional plasma protein, lipid transfer inhibitor protein (LTIP) to modify the functional activity of LTP in a complex mixture of lipoproteins. Transfer assays containing isolated LTP, LTIP, and the three major lipoprotein classes, and assays with intact human plasma supplemented with exogenous LTIP were used. In both assays, the inhibition of CE transfer by LTIP varied markedly depending on the lipoproteins involved and was dependent on LTIP concentration. Inhibition of lipid transfer between a given pair of lipoproteins was similar. However, between lipoprotein pairs the extent of inhibition was very different, varying up to 7-fold. Inhibition followed the order of very low density lipoprotein (VLDL)-low density lipoprotein (LDL) transfers > LDL-high density lipoprotein (HDL) transfers > VLDL-HDL transfers. Consistent with the preferential inhibition of transfer events involving LDL, LTIP was shown by gel filtration studies to associate primarily with LDL in plasma. The addition of LTIP to native plasma stimulated the LTP-mediated efflux of CE from HDL to VLDL; this occurred at the expense of LDL CE depletion. Thus, LTIP alters the pattern of lipid transfer reactions in plasma by uniquely affecting the individual transfer events mediated by LTP. By preferentially diminishing transfer events involving LDL, especially those between VLDL and LDL, LTIP enhances the ability of LTP to remove CE from HDL, and thus alters HDL metabolism.

Blood Proteins↗
PubMed1978

Comparison of the phospholipase activity of bovine milk lipoprotein lipase against rat plasma very low density and high density lipoprotein.

The hydrolytic activity of a lipoprotein lipase from bovine milk against triacylglycerol and phosphatidylcholine of rat plasma very low density lipoprotein was determined and compared to that against phosphatidylcholine of high density lipoprotein. 85--90% of the triacylglycerol in very low density lipoprotein were hydrolyzed to fatty acids and 25--35% of the phosphatidylcholine to lysophosphatidylcholine. High density lipoprotein phosphatidylcholine was only minimally susceptible to the enzyme. Even with high amounts of enzyme and prolonged incubation periods, lysophosphatidylcholine generation did not exceed 2--4% of the original amounts of labeled phosphatidylcholine in the high density lipoprotein. We conclude that phospholipids in high density lipoprotein are not substrates for the phospholipase activity of this lipoprotein lipase. These observations suggest that factors other than the presence of apolipoprotein C-II and of glycerophosphatides are of importance for the activity of lipoprotein lipases.

Animals↗