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PubMed2002

An increased number of very-low-density lipoprotein particles is strongly associated with coronary heart disease in Japanese men, independently of intermediate-density lipoprotein or low-density lipoprotein.

BACKGROUND: Japanese patients with coronary heart disease (CHD) usually have slightly elevated triglyceride levels but virtually normal low-density lipoprotein (LDL)-cholesterol levels. DESIGN: Case-control study. METHODS: To explore the atherogenecity of mild hypertriglyceridemia, we measured very-low-density lipoprotein (VLDL) composition and apolipoprotein (apo) B in VLDL, intermediate-density lipoprotein (IDL), light LDL and dense LDL fractions separated by ultracentrifugation in 61 men with angiographically proven CHD and in 69 men without CHD. Apo B, E, C1 and C3 in VLDL were measured by enzyme-linked immunosorbent assay. RESULTS: Although total- and LDL-cholesterol levels were similar in CHD and control participants, triglyceride levels were significantly higher and high-density lipoprotein (HDL)-cholesterol levels were lower in CHD patients. Triglyceride, cholesterol and apo C1 and E levels in VLDL were two-fold higher and VLDL-apo B level was three-fold higher in CHD than control patients. IDL-triglyceride levels were significantly elevated in CHD, but IDL-cholesterol level was not. Apo B levels of the dense LDL fraction were significantly elevated in CHD groups, but those of the light LDL fraction were not. These differences were constant when triglyceride levels matched between both groups. Multiple logistic regression analysis revealed that the VLDL-apo B and VLDL-apo C1 levels were significantly associated with the incidence of CHD independent of the plasma triglyceride, HDL-cholesterol or apo B levels in dense LDL. CONCLUSION: These results suggest that an increased number of VLDL particles is strongly associated with CHD, independently of traditional risk factors or newly recognized atherogenic lipoproteins, such as IDL or small, dense LDL, in Japanese men.

Apolipoproteins B↗
PubMed1993

The alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein binds lipoprotein lipase and beta-migrating very low density lipoprotein associated with the lipase.

Lipoprotein lipase (LPL) causes a marked increase in the cellular binding of beta-migrating very low density lipoprotein (beta-VLDL) to a large receptor compatible with the alpha 2-macroglobulin receptor (alpha 2MR)/low density lipoprotein receptor-related protein (LRP) (Beisiegel, U., Weber, W., and Bengtsson-Olivecrona, G. (1991) Proc. Natl. Acad. Sci. U. S. A. 88, 8342-8346). Here we demonstrate that LPL binds to the alpha-chain of purified alpha 2MR/LRP immobilized on microtiter plates. The binding, apparently to multiple sites, was blocked by heparin and inhibited by the alpha 2MR-associated protein (alpha 2MRAP) and by EDTA. Immobilized LPL bound alpha 2MR/LRP in solution as well as beta-VLDL prepared from cholesterol-fed rabbits. Both binding reactions were dependent on an intact carboxyl-terminal folding domain of LPL, but were independent of its dimeric structure and intact catalytical function. Dimeric LPL could mediate binding of beta-VLDL to immobilized alpha 2MR/LRP and to cells, e.g. monocytes. In contrast, LPL monomers were not able to mediate binding to immobilized alpha 2MR/LRP, presumably because of cross-inhibition due to close relation between the binding regions for the lipoprotein and for the receptor in the carboxyl-terminal domain of the LPL monomer. Heparin, but not alpha 2MRAP, inhibited cellular binding of 125I-LPL or 125I-beta-VLDL supplemented with LPL. However, alpha 2MRAP inhibited degradation of the two ligands by about 90% and 40-50%, respectively. The results show that LPL is a ligand for alpha 2MR/LRP and, because of its affinity for lipoprotein particles, dimeric LPL can mediate or strengthen binding of beta-VLDL to this receptor. It is proposed that LPL binds primarily to cell surface heparan sulfate in monocytes and is presented for endocytosis and degradation by alpha 2MR/LRP. Moreover, beta-VLDL may be further supplemented with LPL at the cell surface and achieve affinity for alpha 2MR/LRP.

Animals↗
PubMed2006

Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial.

BACKGROUND: Changes in conventional lipid risk factors with gemfibrozil treatment only partially explain the reductions in coronary heart disease (CHD) events experienced by men in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT). We examined whether measurement of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particle subclasses provides additional information relative to CHD risk reduction. METHODS AND RESULTS: This is a prospective nested case-control study of 364 men with a new CHD event (nonfatal myocardial infarction or cardiac death) during a 5.1-year (median) follow-up and 697 age-matched controls. Nuclear magnetic resonance (NMR) spectroscopy was used to quantify levels of LDL and HDL particle subclasses and mean particle sizes in plasma obtained at baseline and after 7 months of treatment with gemfibrozil or placebo. Odds ratios for a 1-SD increment of each lipoprotein variable were calculated with adjusted logistic regression models. Gemfibrozil treatment increased LDL size and lowered numbers of LDL particles (-5%) while raising numbers of HDL particles (10%) and small HDL subclass particles (21%). Concentrations of these LDL and HDL particles achieved with gemfibrozil were significant, independent predictors of new CHD events. For total LDL and HDL particles, odds ratios predicting CHD benefit were 1.28 (95% CI, 1.12 to 1.47) and 0.71 (95% CI, 0.61 to 0.81), respectively. Mean LDL and HDL particle sizes were not associated with CHD events. CONCLUSIONS: The effects of gemfibrozil on NMR-measured LDL and HDL particle subclasses, which are not reflected by conventional lipoprotein cholesterol measures, help to explain the demonstrated benefit of this therapy in patients with low HDL cholesterol.

Aged↗
PubMed2001

Ex vivo measurement of lipoprotein lipase-dependent very low density lipoprotein (VLDL)-triglyceride hydrolysis in human VLDL: an alternative to the postheparin assay of lipoprotein lipase activity?

The plasma lipolysis of triglyceride (TG)-rich lipoproteins is mainly due to the activity of lipoprotein lipase (LPL). Albeit important for our analysis of certain physiopathological situations, the determination of the magnitude of LPL-dependent lipolysis is not easy to perform. This essentially results from the binding of LPL to the luminal surface of vascular endothelium. The measurements of the whole putative LPL activity have been achieved after injection of heparin, a procedure that releases LPL from endothelium. However, the physiopathological relevance of this postheparin lipolysis assay (PHLA) remains questionable because it has never been demonstrated that the bulk of endothelium-bound LPL was active. It has been recently shown that a small part of LPL is associated to circulating lipoproteins in nonheparinized plasma, raising the possibility that the lipolysis mediated by this circulating LPL might reflect the overall LPL-dependent TG hydrolysis in plasma. To address this question, we developed a new lipolysis assay in which the very low density lipoprotein (VLDL)-bound LPL-dependent VLDL-TG hydrolysis (LVTH) was directly determined through the measurement of nonesterified fatty acid (NEFA) release during in vitro incubations. LVTH measurements were performed in control subjects, in type 2 diabetics, and in either heterozygous or homozygous LPL-deficient patients. In the latter group, LVTH values were extremely low. Those of heterozygous patients and of diabetics were similarly decreased by about 40% with respect to control group. Plasma TG concentrations exhibited an inverse relationship with LVTH level. In a subgroup of subjects, LVTH and PHLA were positively correlated and the inverse correlation of LVTH with plasma or VLDL-TG concentration was stronger than that obtained with PHLA. To further study the validity of this new assay, we measured LVTH in nine subjects who were studied for their catabolism of VLDL labeled with stable isotope. No relation was observed between the direct hepatic removal of VLDL and LVTH, whereas the latter was strikingly correlated with the rate of conversion of VLDL to intermediary density lipoprotein. Collective consideration of these findings strongly suggests that LVTH is a physiologically relevant index which could advantageously replace the measurements of PHLA in numerous physiopathological situations.

Adult↗
PubMed1988

Lipoproteins of the newborn rat. Reciprocal development of low density lipoproteins and apoprotein E-rich high density lipoproteins.

Plasma lipids increase sharply with the onset of suckling in the neonatal rat. Much of the variation has been attributed to the high fat content of milk. Apoproteins AI, E and AIV were found in low concentrations in the fetus. They increased during suckling. Apoprotein E and apoprotein AIV did not exceed adult values whereas apoprotein AI concentration in the late suckling period was twice that of the adult. On the contrast, fetal apoprotein B was nearly 2.5-fold above adult concentration and was under the form of LDL, the main lipoprotein class in the late fetal period. Apoprotein B concentration decreased progressively as LDL was replaced by an apoprotein E-rich HDL. The latter class constituted an important transitory cholesterol carrier during the shift from the neonatal lipoprotein pattern dominated by LDL to the typical adult pattern in which HDL are predominant. Lack of active cholesterol ester transfer protein is believed to be one of the reasons for low LDL concentration in adult rats. However, in vitro incubation of radioactively-labelled HDL cholesteryl esters with rat plasma demonstrated that the juveniles' lipoprotein depleted plasma induced as little transfer of the label from HDL to lower density lipoproteins as that of the adult. Thus a transient cholesteryl ester transfer activity could not have contributed to the composition of the LDL pool in the fetus and the early suckling rat. It is more likely that LDL are secreted directly by the liver. Each apolipoprotein exhibited a characteristic developmental pattern different from that of adult rats fed hyperlipidic diets. It therefore appears that each apoprotein is controlled independently by a combination of programmed ontogenic development and nutritional factors leading to the progressive establishment of the adult lipoprotein profile.

Animals↗
PubMed1984

Low-density lipoprotein receptor binding determinants switch from apolipoprotein E to apolipoprotein B during conversion of hypertriglyceridemic very-low-density lipoprotein to low-density lipoproteins.

Using thrombin and trypsin as probes, we determined: first, that low-density lipoprotein (LDL) receptor binding determinants switch from apolipoprotein (apo) E to apo-B within the very-low-density lipoprotein (VLDL) Sf 20-60 region of the metabolic cascade from VLDL1 (Sf 100-400) of hypertriglyceridemic (HTG) human subjects to LDL. Second, two different conformations of apo-E exist in HTG-VLDL Sf greater than 60, one accessible (greater than or equal to 1 mol/mol of particle) and one inaccessible (1-2 mol/mol) to both thrombin and the LDL receptor; normal VLDL (Sf greater than 60) have only the inaccessible conformation and therefore do not bind to the LDL receptor. Third, thrombin degrades apo-B into large fragments, three of which have electrophoretic mobilities similar to B-48, B-74, and B-26; this, however, has no effect on apo-B-mediated receptor binding. Fibroblast studies showed that thrombin could abolish receptor uptake of HTG-VLDL1 and HTG-VLDL2 (Sf 60-100), had little or no effect on HTG-VLDL3 (Sf 20-60), and no effect on uptake of intermediate-density lipoprotein (IDL) or LDL. Trypsin abolished the binding of HTG-VLDL1 and HTG-VLDL2, reduced that of HTG-VLDL3, but had little to no effect on IDL or LDL binding. Immunochemical techniques revealed that thrombin cleaved some apo-E into the E-22 and E-12 fragments; after trypsin treatment no apo-E was detected in any HTG-lipoprotein. Normal VLDL subclasses contained less apo-E than the corresponding HTG-VLDL subclasses and it was not cleaved by thrombin. Apo-B immunoreactivities of VLDL subclasses were not significantly changed after treatment with thrombin, although thrombin cleaved some of the B-100 of each VLDL subclass, and all apo-B in IDL and LDL, into 4-6 major large fragments. Trypsin converted all of the apo-B of each lipoprotein into smaller fragments (Mr less than 100,000). We conclude that apo-E of the thrombin-accessible conformation mediates uptake of HTG-VLDL1 and HTG-VLDL2 but that apo-B alone is sufficient to mediate receptor binding of IDL and LDL; the switch from apo-E to apo-B as the primary or sufficient binding determinant occurs within the VLDL3 (Sf 20-60) region of the metabolic cascade, where receptor binding first appears in VLDL subclasses from normal subjects.

Apolipoproteins B↗
PubMed1982

Effects of niceritrol (pentaerythritol tetranicotinate) on plasma lipoprotein concentration: increment of high density lipoprotein(HDL) cholesterol and HDL-cholesterol/low density lipoprotein cholesterol ratio in hypo-high density lipoproteinemia.

The purpose of the present study was to investigate the effects of niceritrol on HDL metabolism. In study (A), niceritrol, 750 mg/day was given for initial period of 12 weeks and 1,500 mg/day was prescribed for an additional 12 weeks to 12 subjects. In six of them, the HDL cholesterol (Ch) levels were less than 45 mg/100 ml with normal plasma cholesterol levels and with plasma triglyceride levels of less than 250 mg/100 ml. In the remaining six subjects, HDL-Ch, plasma cholesterol and triglyceride levels were all within normal limits except in one subject having a higher triglyceride level, 213 mg/100 ml. Plasma lipoproteins were fractionated by sequential ultracentrifugation and analyzed for cholesterol, triglyceride (TG), phospholipid(PL), apolipoprotein(Apo) B and Apo A-I, every 4 weeks. Niceritrol decreased plasma-Ch, VLDL-Ch, LDL-Ch, plasma-TG, VLDL-TG, plasma-PL, VLDL-PL and LDL-PL. Niceritrol increased HDL-Ch and the HDL-Ch/LDL-Ch ratio. These effects were more significant for the dose of 1,500 mg/day than 750 mg/day and were more marked in the patients with lower pretreatment HDL-Ch levels. Apo B level at 20 weeks was significantly lower than that before treatment. Initial plasma Apo A-I levels of the patients were approximately one-half of the control plasma. After treatment with niceritrol, Apo A-I concentration tended to increase. In study (B), changes of lipids concentration in HDL2 and HDL3 fraction were investigated in 5 patients during treatment with niceritrol, 1,500 mg/day for 8 weeks. Lipoproteins were analyzed every 2 weeks. HDL2-Ch levels tended to increase without significant changes of HDL3-Ch levels and HDL2-Ch/HDL3-Ch ratio showed a tendency to increase. A significantly but weakly inverse correlation between changes of VLDL-TG and HDL-Ch was observed, suggesting that the increment of HDL might be due partly to promoted lipolysis of TG-rich lipoproteins. However, it was suggested that the effects of niceritrol on lipoprotein synthesis in the liver and HDL catabolism should be considered.

Aged↗
PubMed1991

Influence of early diabetic nephropathy on very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) composition.

The procedure of discontinuous gradient ultracentrifugation (DGU) was used to characterize the influence of early diabetic nephropathy on the composition of very low density lipoprotein (VLDL, flotation density 60-400 Svedberg (Sf) units), low density lipoprotein (LDL, flotation density 0-12 Sf) and subfractions of intermediate density lipoprotein (IDL1 and IDL2, 20-60 and 12-20 Sf, respectively). Forty-six subjects with type 1 (insulin-dependent) diabetes and serum creatinine, less than 140 mumol/l were studied, of whom 23 consistently had normal rates of albumin excretion (AER less than 15 micrograms/min), and 23 had persistent albuminuria (AER 20.0-960.6 micrograms/min). The two groups were similar with respect to total serum lipids, glycaemic control, age and body mass. The composition (lipid, protein and phospholipid) and mass of VLDL, LDL and IDL2 was not appreciably altered by early nephropathy, but free and total cholesterol concentration in IDL1 (Sf 20-60) was increased (total cholesterol 0.68 (0.09) (mean (SE)) vs. 0.47 (0.07) mmol/l, and free cholesterol 0.27 (0.04) vs. 0.17 (0.03) mmol/l, both P less than 0.05). The explanation of these findings was probably an accumulation in the circulation of the remnants of chylomicron metabolism and/or intermediates in the conversion from VLDL to IDL1. In addition, there was a decrease in serum high density lipoprotein (HDL) cholesterol in early nephropathy (1.27 (0.06) vs. 1.38 (0.10) mmol/l, P less than 0.05), due to a decrease in the HDL2 cholesterol subfraction (P less than 0.05). These findings may in part explain the increased risk of premature atherosclerosis associated with the development of albuminuria.

Adolescent↗
PubMed1990

Role of lipoprotein lipase in the regulation of high density lipoprotein apolipoprotein metabolism. Studies in normal and lipoprotein lipase-inhibited monkeys.

Mechanisms that might be responsible for the low levels of high density lipoprotein (HDL) associated with hypertriglyceridemia were studied in an animal model. Specific monoclonal antibodies were infused into female cynomolgus monkeys to inhibit lipoprotein lipase (LPL), the rate-limiting enzyme for triglyceride catabolism. LPL inhibition produced marked and sustained hypertriglyceridemia, with plasma triglyceride levels of 633-1240 mg/dl. HDL protein and cholesterol and plasma apolipoprotein (apo) AI levels decreased; HDL triglyceride (TG) levels increased. The fractional catabolic rate of homologous monkey HDL apolipoproteins injected into LPL-inhibited animals (n = 7) was more than double that of normal animals (0.094 +/- 0.010 vs. 0.037 +/- 0.001 pools of HDL protein removed per hour, average +/- SEM). The fractional catabolic rate of low density lipoprotein apolipoprotein did not differ between the two groups of animals. Using HDL apolipoproteins labeled with tyramine-cellobiose, the tissues responsible for this increased HDL apolipoprotein catabolism were explored. A greater proportion of HDL apolipoprotein degradation occurred in the kidneys of hypertriglyceridemic than normal animals; the proportions in liver were the same in normal and LPL-inhibited monkeys. Hypertriglyceridemia due to LPL deficiency is associated with low levels of circulating HDL cholesterol and apo AI. This is due, in part, to increased fractional catabolism of apo AI. Our studies suggest that variations in the rate of LPL-mediated lipolysis of TG-rich lipoproteins may lead to differences in HDL apolipoprotein fractional catabolic rate.

Animals↗
PubMed2004

Expression of mRNA of lipoprotein receptor related protein 8, low density lipoprotein receptor, and very low density lipoprotein receptor in bovine ovarian cells during follicular development and corpus luteum formation and regression.

Lipoproteins in the plasma are the major source of cholesterol obtained by the ovarian theca and granulosa cells for steroidogenesis. In this study, we have identified mRNA expression in bovine theca and granulosa cells of two lipoprotein receptors, low density lipoprotein receptor (LDLr) and very low density lipoprotein receptor (VLDLr) in granulosa cells from small antral follicles through preovulatory follicles and in theca cells from large and medium sized antral follicles. In the corpus luteum (CL) both these receptors were found in the developing and differentiating stages whereas only mRNA for VLDLr was detected in the regression stage. This study also described for the first time, the presence of lipoprotein receptor related protein (LRP8) in granulosa cells from small antral follicles through preovulatory follicles and in theca cells from large and medium sized antral follicles. This may indicate a role of LRP8 in cholesterol delivery to steriodogenic cells. LRP8 was not detected in any of the CL stages. The roles of the LDLr superfamily in lipid transport to ovarian cells and its participation in follicular and CL development and regression is discussed.

Animals↗
PubMed1996

Beyond low-density lipoprotein cholesterol. A perspective on low high-density lipoprotein disorders and Lp(a) lipoprotein excess.

Evidence supports the involvement of 2 common dyslipidemias---low high-density lipoprotein disorders and Lp(a) lipoprotein excess--in coronary heart disease. Until clinical trials determine whether specific therapeutic interventions can prevent the occurrence and recurrence of coronary heart disease in patients with these dyslipidemias, the implementation of cholesterol-lowering guidelines can provide a reasonable way to manage low high-density lipoprotein disorders and to identify specific categories of patients who may be at particularly high risk for premature coronary heart disease. Empiric treatment guidelines are suggested for low high-density lipoprotein disorders and Lp(a) lipoprotein excess in order to foster further discussion and validation by clinical trial data.

Cholesterol, HDL↗
PubMed1988

Familial lipoprotein lipase deficiency: abnormal lipoproteins and defective metabolism of low density lipoproteins in cultured human skin fibroblasts.

Lipoproteins (chylomicrons + VLDL, VLDL, IDL, LDL and HDL) were separated from the plasma of 2 patients with primary, familial lipoprotein lipase deficiency. Chylomicrons were excessively enriched with cholesteryl esters. VLDL and IDL were of almost normal composition. LDL separated into 2 fractions LDL1 and LDL2, both triglyceride- and protein-rich and cholesteryl ester-poor. LDL2, the main LDL fraction, was denser and smaller than normal LDL. HDL3 was the only HDL population identified and was also triglyceride- and protein-rich and cholesteryl ester-poor. These observations indicate excessive triglyceride and cholesteryl ester transfer between chylomicrons and LDL and HDL. VLDL and its immediate catabolic product, IDL, seem to be spared the effects of the lipid transfer reaction. The biological reactivity of LDL1 and LDL2 was investigated in upregulated cultured human skin fibroblasts. Both exhibited defective specific binding to the LDL receptor and ineffective capacity to down-regulate sterol synthesis. These abnormalities were more pronounced with LDL3. The ineffective downregulation of sterol synthesis is most probably due to both the cholesterol content of the LDLs and their reduced binding to the LDL receptor. The defective binding of the LDLs to the receptor can be attributed to the abnormal composition of the lipoproteins and, to a lesser degree, reduced diameters (only LDL2). It is concluded that abnormal composition of LDL, in particular of lipid moieties, may change the affinity of the moiety of the lipoprotein towards the LDL receptor.

Adult↗
PubMed1993

Composition of human low density lipoprotein: effects of postprandial triglyceride-rich lipoproteins, lipoprotein lipase, hepatic lipase and cholesteryl ester transfer protein.

A preponderance of small, dense low density lipoprotein (LDL) particles has been linked to increased risk of myocardial infarction, and a dense and protein-rich LDL has proved to be a characteristic of patients with manifest coronary heart disease (CHD). The present study focused on metabolic determinants of the LDL subfraction distribution with the emphasis placed on alimentary lipaemia. The relations of plasma levels and composition of light (1.019 < d < 1.040 kg/l) and dense (1.040 < d < 1.063 kg/l) LDL subfractions to postprandial triglyceride-rich lipoproteins (TGRL), postheparin plasma lipase activities and the activity of cholesteryl ester transfer protein (CETP) were studied in 32 men with angiographically ascertained premature coronary atherosclerosis (age 48.8 +/- 3.2 years) and in 10 age matched healthy control men. LDL subfractions were separated by equilibrium density gradient ultracentrifugation of fasting plasma drawn before participants were subjected to an oral fat tolerance test of a mixed meal type. The response of TGRL to the oral fat load was determined by measuring plasma triglycerides, and the apolipoprotein (apo) B-48 and apo B-100 content of Sf 60-400 and Sf 20-60 lipoprotein fractions. At a second visit plasma samples were taken for determination of postheparin plasma lipoprotein lipase (LPL) and hepatic lipase (HL) activities and for measurement of CETP activity. Hypertriglyceridaemic patients had a preponderance of dense LDL particles compared with normotriglyceridaemic patients and controls. The magnitude of the response of TGRL to the oral fat load showed a positive association with the dense LDL apo B concentration (r = 0.32-0.52, P < 0.05), whereas the LPL activity correlated positively with the free (r = 0.50, P < 0.001) and esterified cholesterol (r = 0.45, P < 0.01) and apo B (r = 0.42, P < 0.01) content of the light LDL fraction. The HL activity was found to be inversely associated with the plasma level of light LDL triglycerides (r = -0.38, P < 0.05). In contrast, no relations were noted between CETP activity and plasma concentrations of LDL constituents. Multiple stepwise linear regression analysis with the proportion of total LDL apo B contained in the dense LDL subfraction (% dense LDL apo B) used as the dependent variable indicated that the combined effect of LPL activity and postprandial plasma levels of TGRL (areas under the curve for plasma triglycerides or Sf 60-400 apo B-48) accounted for around 50% of the variability in the distribution of LDL particles between light and dense subfractions.(ABSTRACT TRUNCATED AT 400 WORDS)

Carrier Proteins↗
PubMed2003

Effects of short- and long-term growth hormone replacement on lipoprotein composition and on very-low-density lipoprotein and low-density lipoprotein apolipoprotein B100 kinetics in growth hormone-deficient hypopituitary subjects.

In this study, we concurrently examined the effects of 8 and 40 weeks of growth hormone replacement (GHR) on lipids, lipoprotein composition, low-density lipoprotein (LDL) size, very-low-density lipoprotein (VLDL) apolipoprotein (apo)B kinetics and LDL apoB kinetics. Eight weeks of GHR did not alter lipid profiles. Forty weeks of GHR increased high-density lipoprotein-cholesterol (HDL-C) concentration (P =.01), nonsignificantly reduced LDL-C (P =.06), and reduced the HDL/LDL-C ratio (P =.04). Forty weeks of GHR increased HDL free cholesterol (P =.03), total cholesterol (P =.01), and cholesterol ester (P <.01) concentrations. No other significant changes in VLDL, LDL, or HDL composition or LDL size were noted at any time. Eight weeks of GHR reduced VLDL apoB absolute secretion rate (ASR, P =.03), with nonsignificant reductions in fractional secretion rate (FSR, P =.09) and pool size (P =.09). After 40 weeks of GHR, the VLDL apoB ASR, FSR, and pool size were not significantly different from baseline. Forty weeks of GHR increased both LDL apoB FSR (P =.02) and LDL apoB ASR (P =.04), with a small decrease in pool size. Thus, GHR may have important antiatherogenic effects; HDL-C increased, LDL-C was nonsignificantly reduced, the total/HDL-C ratio was reduced, VLDL apoB production was reduced, and LDL apoB turnover was increased.

Adult↗
PubMed1993

High density lipoprotein subfractions, apolipoprotein A-I containing lipoproteins, lipoprotein (a), and cholesterol ester transfer protein activity in alcoholic women before and after ethanol withdrawal.

We studied 11 female alcoholics before and after ethanol withdrawal of 2 weeks and 10 healthy normolipidaemic, nonalcoholic women of similar age. In alcoholic women the HDL2 mass was increased by 63% (P < 0.01) on admission and normalized (P < 0.01) during abstention. The concentrations of HDL3 cholesterol and its mass remained unchanged throughout the study. Consistently with the fall of HDL2 gradient gel electrophoresis analyses also demonstrated decrease of the cholesterol concentration of HDL2b and HDL2a (P < 0.05) during alcohol withdrawal. On admission the apo A-II concentration was increased by 48% (P < 0.01) and it was normalized (P < 0.001) during abstention. Among apo A-I containing lipoproteins the most prominent change occurred in Lp A-I:A-II, which fell by 32% (P < 0.01) during 1 week's alcohol withdrawal. During abstention the lipoprotein (a) concentration increased in 10 out of 11 women. In patients cholesteryl ester transfer (CETP) activity increased by 35% (P < 0.01) during 1 week of ethanol withdrawal. On admission postheparin plasma lipoprotein (LPL) and hepatic lipase activities were increased by 25% (P = NS); during 1 week's abstention they both returned to the control level (P < 0.05- < 0.01). In conclusion, chronic alcoholic women display multiple changes of lipoprotein metabolism which are rapidly reversed during abstinence. In contrast to alcoholic men, studied previously by us using the same study design and methods, there was no significant elevation of HDL3 cholesterol and apo A-I. The data suggest that alcohol interferes with several regulatory steps of HDL metabolism which are partly gender dependent.

Adult↗
PubMed2003

[Effects of plasma very low density lipoprotein, low density lipoprotein and high density lipoprotein on platelet aggregation in endogenous hypertriglyceridemia].

OBJECTIVE: To study whether plasma very low density lipoprotein (VLDL), low density lipoprotein (LDL), high density lipoprotein (HDL) were oxidatively modified in endogenous hypertriglyceridemia (HTG) and to investigate the effects of HTG VLDL, LDL and HDL on platelet aggregation in vitro. METHODS: Blood samples were taken from 21 patients with endogenous triglyceridemia and 21 normal healthy subjects; these two groups were similar in respect to age and sex. Their plasma VLDL, LDL and HDL were isolated by density gradient ultracentrifugation method, and plasma triglycerides (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDLC) were measured by enzyme method. The oxidative modification of LDL, VLDL and HDL was identified by agarose gel relative electrophoretic mobility (REM), absorbance at 234 nm (A234) and fluorescence of thiobarbituric acid reaction substances (TBARS). With the reaction system that consisted of mixed fresh normal plasma, platelet aggregation was induced by adenosine diphosphate (ADP), and the platelet maximal aggregation rate (MAR) was recorded on a 4-channel light aggregometer. RESULTS: The plasma TG, TBARS levels in HTG group were 1.6 and 0.4 times over those of the control group respectively (P < 0.01). The plasma HDLC in HTG group was 32% lower than those of the control group (P < 0.01). REM, A234 and TBARS of VLDL, LDL and HDL in HTG group were significantly higher than those in the control group (P < 0.01). MAR of VLDL, LDL and HDL in HTG group were significantly higher than those in the control group (P < 0.05). The correlation analysis indicated that REM, A234 and TBARS of LDL and HDL in HTG group were positively correlated with MAR (P < 0.01). CONCLUSION: The above data indicated that oxidative modification of plasma VLDL, LDL, HDL did occur in endogenous hypertriglyceridemia in vivo, and VLDL, LDL and HDL enhanced platelet aggregation in vitro.

Aged↗
PubMed1994

Cellular catabolism of normal very low density lipoproteins via the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor is induced by the C-terminal domain of lipoprotein lipase.

Lipoprotein lipase (LPL) binds to the low density lipoprotein receptor-related protein (LRP)/alpha 2-macroglobulin receptor and induces catabolism of normal human very low density lipoproteins (VLDL) via LRP in vitro. Recent studies showed that the C-terminal domain of LPL can bind LRP in solid phase assays and inhibit cellular catabolism of two LRP ligands, activated alpha 2-macroglobulin and the 39-kDa receptor-associated protein (Williams, S.E., Inoue, I., Tran, H., Fry, G. L., Pladet, M.W., Iverius, P.-H., Lalouel, J.-M., Chappell, D.A., and Strickland, D.K. (1994) J. Biol. Chem. 269, 8653-8658). The current study investigated the potential for this region of LPL to promote cellular catabolism of VLDL via LRP. A fragment comprising the C-terminal domain of LPL (designated LPLC) was expressed in bacteria and found to promote cellular binding, uptake, and degradation of normal human VLDL in a dose-dependent manner. These effects were present whether LPLC was added simultaneously with 125I-VLDL or was prebound to cell surfaces prior to the assay. Mutations involving Lys407, Trp393, Trp394, or deletion of the C-terminal 14 residues reduced the effects of LPLC. Three LRP-binding proteins, the receptor-associated protein, lactoferrin, and a polyclonal antibody against LRP, competed for 125I-VLDL degradation induced by LPLC. Heparin or heparinase treatment of cells prevented LPLC-induced 125I-VLDL catabolism. Thus, cell-surface proteoglycans play an important role in this pathway. Interestingly, either LPLC or LPL when added in excess could block LPL-induced 125I-VLDL degradation presumably by interacting directly with LRP. However, unlabeled VLDL could not prevent catabolism of 125I-labeled LPLC or LPL. These data show that cellular fates for VLDL versus LPLC or LPL are divergent. This is probably due to independent catabolism of the latter via cell-surface proteoglycans. In summary, these in vitro studies indicate that a fragment of LPL corresponding to the C-terminal domain mimics the native enzyme with respect to induction of VLDL catabolism via LRP. Because LPLC lacks the catalytic site of native LPL, these studies establish that lipase activity is not required for LRP-mediated lipoprotein catabolism.

Binding, Competitive↗
PubMed1997

Immunoenzyme assessment of human apoB-lipoprotein binding to immobilized receptor of low density lipoproteins. 2. Binding of isolated lipoproteins.

The receptor of low density lipoproteins (LDL-receptor) from bovine adrenal cortex membranes was immobilized in standard 96-well polystyrene plates using monoclonal V5-antibodies to the LDL-receptor. The binding of the immobilized LDL-receptor with human low density lipoproteins (LDL) and very low density lipoproteins (VLDL) was determined using peroxidase-labelled antibodies to human apoB. The value of Kd for the interaction of LDL with the immobilized LDL-receptor for 40 samples of LDL was found to be from 5 to 20 micrograms apoB per ml. The immobilized LDL-receptor failed to bind LDL modified by acetylation or malonic dialdehyde, while the binding of non-modified LDL to the immobilized LDL-receptor was inhibited in the presence of EDTA, which is known to be specific for the interaction of LDL with the LDL-receptor. Unlike LDL, VLDL were more variable in the binding to the LDL-receptor. The value of Kd for the interaction of VLDL with the LDL-receptor for 40 samples of VLDL was found to be from 0.5 to 10 micrograms apoB per ml. Thus, the described method is suggested to study the interaction of apoB-containing lipoproteins with the LDL-receptor.

Acetylation↗