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PubMed1995

ELISA quantitation of apolipoproteins in plasma lipoprotein fractions: ApoE in ApoB-containing lipoproteins (Lp B:E) and ApoB in ApoE-containing lipoproteins (Lp E:B).

Growing clinical evidence suggests that metabolic behavior and atherogenic potential vary within lipoprotein subclasses that can be defined by apolipoprotein variation. Variant constituency of apolipoproteins B and E (apoB and apoE) may be particularly important because of the central roles of these apolipoproteins in the endogenous lipid delivery cascade. ApoB is the sole protein of low-density lipoprotein (LDL), and like LDL cholesterol, the plasma apoB level has been positively correlated with risk for atherosclerotic disease. ApoE is a major functional lipoprotein in the triglyceride-rich lipoproteins, and may be crucial in the conversion of very low density lipoprotein (VLDL) to LDL. Based on work by others that enabled the quantititation of apoB-containing particles by content of up to two other types of apolipoprotein, we have developed a method for determining the amount of apoE in apoB-containing lipoproteins (Lp B:E) and the amount of apoB in apoE-containing lipoproteins (Lp E:B). From the Lp B:E and Lp E:B concentrations, the molar ratio of apoE to apoB in lipoproteins containing apoB and/or apoE in plasma can be determined. The methodology is fast, specific, and sensitive and should prove extremely useful in further categorizing lipoproteins and characterizing their behavior. In applying this method to clinical groupings of normo- and hyperlipidemia, we found that the plasma triglyceride level correlated with the apoE and Lp B:E concentrations in plasma, while the total cholesterol level correlated with the apoB and Lp E:B levels.

Antibody Specificity↗
PubMed2004

Ability of non-high-density lipoprotein cholesterol and calculated intermediate-density lipoprotein to identify nontraditional lipoprotein subclass risk factors in dialysis patients.

BACKGROUND: Non-high-density lipoprotein cholesterol (non-HDL-C) and calculated intermediate-density lipoprotein cholesterol (IDL-C) have been proposed as surrogate markers to estimate apolipoprotein B-containing lipoproteins. The purpose of this study was to determine the validity of non-HDL-C and calculated IDL-C to predict nontraditional lipoprotein risk factors among dialysis patients and to compare the prevalence of these nontraditional risk factors between dialysis modalities. METHODS: The authors performed a cross-sectional analysis comparing standard lipid profile with lipoprotein analysis via nuclear magnetic resonance (NMR) spectroscopy among 186 hemodialysis (HD) and peritoneal dialysis (PD) patients on modern lipid-lowering therapy. RESULTS: The PD group had a significantly higher low-density lipoprotein (LDL) particle concentration (P < 0.005), higher large very low-density lipoprotein (VLDL; P < 0.001), greater small dense LDL (P < 0.001), and lower protective large HDL (P < 0.005). Forty-six (40%) of 118 subjects with LDL-C below goal had at least 1 nontraditional risk factor by NMR spectroscopy. The sensitivity of non-HDL-C method together with triglyceride (TG) value greater than 200 mg/dL (>2.26 mmol/L) to predict nontraditional risk was 13% and increased to 20% if TG values were excluded. A negative correlation was observed between LDL particle size and HDL-C (r2 = 0.269; P < 0.001); the sensitivity of HDL-C to predict LDL size was 92%. There was no relationship between measured IDL by NMR and calculated IDL-C (r2 = 0.005; P = 0.69). CONCLUSION: Non-HDL-C greater than 130 mg/dL (3.4 mmol/L) independent of TG values and HDL-C lower than 40 mg/dL (1.0 mmol/L) may predict nontraditional lipoprotein risk factors among dialysis patients. This is especially applicable to patients on PD, a modality associated with a more atherogenic lipoprotein profile.

Aged↗
PubMed1990

Free cholesterol transfer from human lower-density lipoproteins (d less than 1.063) to lipoprotein-deficient serum and high-density lipoproteins.

The in vitro transfer of free cholesterol (FC) between human serum lipoproteins in the absence of lecithin:cholesterol acyltransferase (LCAT) activity has been examined. The results show that the amount of FC that the high-density lipoprotein (HDL) and lipoprotein-deficient serum (LDS) fractions were able to capture from low-density lipoproteins (LDL) and very-low-density lipoproteins (VLDL) was proportional to the amount of FC present in d less than 1.063 lipoproteins. The presence of HDL increased this transfer markedly. These results indicate that, in the absence of LCAT activity, FC can transfer from lower-density lipoproteins to higher-density serum fractions, and this transfer might increase under hypercholesterolemic conditions. The possible importance of this phenomena in regard to the exchange of FC between serum lipoproteins and tissue cells is discussed.

Chemical Precipitation↗
PubMed2004

Lipoprotein heterogeneity at birth: influence of gestational age and race on lipoprotein subclasses and Lp (a) lipoprotein.

OBJECTIVE: To determine the influence of gestational age, gender, and race, on lipoprotein heterogeneity at birth. DESIGN: Prospective study of representative sample of infants. SETTING: The Johns Hopkins Hospital. PARTICIPANTS: 163 infants (70 White and 93 Black) >28 weeks gestational age. INTERVENTION: None. MAIN OUTCOME MEASURES: Lipids, lipoprotein subclasses, apolipoproteins, Lp (a) lipoprotein. RESULTS: The number of low-density lipoprotein (LDL) particles, large LDL subclass, and LDL cholesterol level, were all significantly higher in the younger infants. The large high-density lipoprotein (HDL) subclass was significantly higher, while the small HDL subclass was significantly lower in the younger infants. Female infants had a greater HDL size than did males (P=.03). There were no differences between the age groups for HDL cholesterol, very low-density lipoprotein subclasses, or levels of triglycerides, or apolipoproteins B and A-I. White infants had a notably higher mean (SD) level (nmol/L) of total LDL particles (476 [251]), compared to the Black infants (372 [177]) (P=.009). The Black infants had a significantly (P=.02) higher mean (SD) Lp (a) lipoprotein level (mg/dL), compared to the White infants, 2.8 (3.2) vs 1.7 (2.4). Black small-for-gestational age infants had significantly higher levels of very low and intermediate density lipoproteins and apolipoprotein B, compared to appropriate-for-gestational age infants. CONCLUSIONS: Gestational age has a significant effect on both LDL and HDL subclasses. Differences in LDL particle number and Lp (a) between White and Black infants mirror those seen later in life.

Age Factors↗
PubMed2001

Cyclosporine A transfer between high- and low-density lipoproteins: independent from lipid transfer protein I-facilitated transfer of lipoprotein-coated phospholipids because of high affinity of cyclosporine a for the protein component of lipoproteins.

The objectives of this study were to determine if lipid transfer protein I (LTP I)-facilitated phospholipid (PC) transfer activity regulates the plasma lipoprotein distribution of cyclosporine (CSA) and if the association of CSA with high-density lipoproteins (HDL) is due to the high protein and/or alterations in coat lipid content of HDL. To assess if LTP I-facilitated PC transfer activity regulates the plasma lipoprotein distribution of CSA, (14)C-PC- or (3)H-CSA-enriched HDL or low-density lipoproteins (LDL) were incubated in T150 buffer [pH 7.4, containing a (14)C-PC- or (3)H-CSA-free lipoprotein counterpart +/- exogenous LTP I (1.0 microg protein/mL)] or in delipidated human plasma that contained 1.0 microg protein/mL of endogenous LTP I in the presence or absence of a monoclonal antibody TP1 (30 microg protein/mL) directed against LTP I for 90 min at 37 degrees C. To assess the influence of HDL subfraction lipid composition and structure on the plasma distribution of CSA, CSA at 1000 ng of drug/mL of plasma was incubated in human plasma pretreated for 24 h with a lecithin:cholesterol acyltransferase (LCAT) inhibitor, dithionitrobenzoate (DTNB; 3 mM). To assess the binding of CSA to apolipoproteins AI, AII, and B, increasing concentrations of CSA were added to a constant concentration of either apolipoprotein AI, AII, or B. Equilibrium dialysis was used to determine free and bound fractions and Scatchard plot analysis was used to determine binding coefficients. To assess the influence of hydrophobic core lipid volume on the plasma distribution of CSA, CSA was incubated in plasma from patients with well-characterized dyslipidemias. The hydrophobic core lipid volume (CE + TG) within each lipoprotein subfraction was correlated to the amount of CSA recovered in each plasma sample from the different human subjects. The percent transfer of PC from LDL to HDL was different than the percent transfer of CSA in T150 buffer or human plasma source. In the presence of TP1, only PC transfer from LDL to HDL decreased. For plasma incubated with CSA and separated into HDL(2) and HDL(3), 35-50% of drug originally incubated was recovered in the HDL(3) fraction, with the remaining drug being found within the other fractions. When CSA was incubated in plasma pretreated with DTNB, the percentage of CSA recovered in the HDL(3) and HDL(2) fractions was not significantly different compared with that in the HDL(3) and HDL(2) fractions from untreated control plasma. CSA distribution into HDL inversely correlated with the hydrophobic core lipid volume of HDL, whereas distribution into LDL and triglyceride-rich lipoproteins directly correlated with their respective hydrophobic core lipid volumes. We further observed that CSA has high binding affinity and multiple binding sites with apolipoproteins AI (k(d) = 188.9 nM; n = 2), AII (k(d) = 184.7 nM; n = 2), and B (k(d) = 191 nM; n = 3). These findings suggest that the transfer of CSA between different lipoprotein particles is not influenced by LTP I-facilitated PC transfer activity probably because of the high affinity of CSA for the protein components of HDL and LDL.

Carrier Proteins↗
PubMed1995

Treatment of primary mixed hyperlipidemia with etophylline clofibrate: effects on lipoprotein-modifying enzymes, postprandial lipoprotein metabolism, and lipoprotein distribution and composition.

In 17 patients with primary mixed hyperlipidemia we studied levels and composition of lipoproteins in fasting plasma, lipoprotein-modifying enzymes, and postprandial lipoprotein metabolism after an oral fat-tolerance test supplemented with vitamin A before, and 12 weeks after treatment with etophylline clofibrate. With treatment, fasting plasma cholesterol, triglycerides, and the levels of very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and low density lipoproteins (LDL) decreased significantly; high density lipoprotein (HDL) cholesterol increased significantly. Treatment caused also an increase in the protein content of IDL, a decrease in the triglyceride content of LDL, and an increase in the size of LDL as assessed by gradient gel electrophoresis. Concentrations of triglycerides, chylomicrons, and chylomicron remnants after an oral fat load supplemented with vitamin A decreased by 33%, 30% and 6%, respectively (P < 0.005; P < 0.01; and P < 0.05). The activity of lipoprotein lipase and hepatic lipase in postheparin plasma increased by 51% and 45%, respectively (P < 0.01; P < 0.05). We found a decrease in the mass concentration of cholesteryl ester transfer protein (P < 0.05). Stepwise multiple regression analysis showed that the triglyceride content of LDL is determined primarily by fasting triglycerides (r = + 0.53, P < 0.05;baseline) and cholesteryl ester transfer protein (r = + 0.49, P < 0.05; 12 weeks); in contrast, the triglyceride content of HDL3 is determined exclusively by accumulation of postprandial triglycerides (r = + 0.67; P < 0.05; baseline) and postprandial chylomicrons (r = +0.87; P < 0.005; 12 weeks). We conclude that hypolipidemic treatment with etophylline clofibrate favorably affects the cardiovascular risk factor profile in primary mixed hyperlipidemia.

Carrier Proteins↗
PubMed1998

Apolipoprotein E2 reduces the low density lipoprotein level in transgenic mice by impairing lipoprotein lipase-mediated lipolysis of triglyceride-rich lipoproteins.

Apolipoprotein (apo) E2 is often associated with low levels of low density lipoprotein (LDL) cholesterol and high levels of plasma triglycerides in humans. Mice expressing apoE2 also have low LDL levels. To evaluate the possible role of the LDL receptor in the cholesterol-lowering effect of apoE2, we bred transgenic mice expressing low levels of apoE2 with LDL receptor-null mice (hE2(+/0), LDLR-/-). Even in the absence of the LDL receptor, plasma total and LDL cholesterol levels decreased progressively with increasing levels of plasma apoE2. At plasma apoE2 levels >20 mg/dl, LDL cholesterol was approximately 45% lower than in LDLR-/- mice. Thus, the LDL cholesterol-lowering effect of apoE2 is independent of the LDL receptor. In contrast, plasma triglyceride levels increased (mostly in very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL)) progressively as apoE2 levels increased. At plasma apoE2 levels >20 mg/dl, triglycerides were approximately 150% higher than in LDLR-/- mice. Furthermore, in apoE-null mice (hE2(+/0), mE-/-), apoE2 levels also correlated positively with plasma triglyceride levels, suggesting impaired lipolysis in both hE2(+/0),LDLR-/- and hE2(+/0),mE-/- mice. Incubating VLDL or IDL from the hE2(+/0),LDLR-/- or the hE2(+/0),mE-/- mice with mouse postheparin plasma inhibited lipoprotein lipase-mediated lipolysis of apoE2-containing VLDL and IDL by approximately 80 and approximately 70%, respectively, versus normal VLDL and IDL. This observation was confirmed by studies with triglyceride-rich emulsion particles, apoE2, and purified lipoprotein lipase. Furthermore, apoE2-containing VLDL had much less apoC-II than normal VLDL. Adding apoC-II to the incubation partially corrected the apoE2-impaired lipolysis in apoE2-containing VLDL or IDL and corrected it completely in apoE2-containing emulsion particles. Thus, apoE2 lowers LDL cholesterol by impairing lipoprotein lipase-mediated lipolysis of triglyceride-rich lipoproteins (mostly by displacing or masking apoC-II). Furthermore, the effects of apoE2 on both plasma cholesterol and triglyceride levels are dose dependent and act via different mechanisms. The increase in plasma cholesterol caused by apoE2 is due mostly to impaired clearance, whereas the increase in plasma triglycerides is caused mainly by apoE2-impaired lipolysis of triglyceride-rich lipoproteins.

Animals↗
PubMed1998

An apolipoprotein E synthetic peptide targets to lipoproteins in plasma and mediates both cellular lipoprotein interactions in vitro and acute clearance of cholesterol-rich lipoproteins in vivo.

Apolipoprotein (apo) E mediates lipoprotein binding to cellular lipoprotein receptors. Previously we reported that a synthetic peptide representing a linear dimeric repeat of amino acids 141-155 binds cellular LDL receptors. To prepare an apoE peptide that bound to both cholesterol-rich lipoproteins and lipoprotein receptors, an NH2-terminal acetylated apoE dimer peptide was synthesized. This acetylated peptide preferentially associated with lipoproteins in plasma, whereas nonacylated peptides were poor lipid binders. Acetylated peptide/LDL complexes (molar ratios of 4-5:1) enhanced the interaction of LDL with cultured human fibroblasts by 7-12-fold. Participation by both receptors and cell surface heparin sulfate proteoglycans was observed. When a preformed peptide/125I-LDL complex was injected intravenously into C57BL/6J apoE-deficient mice, its rate of removal was threefold higher than that of 125I-LDL alone. The liver and the spleen were major tissue distribution sites. Intravenous administration of free acetylated peptide resulted in a 30% reduction in total plasma cholesterol within 3-30 min, which reflected a 40-50% and 20-26% reduction in very low density lipoproteins and intermediate density lipoproteins, respectively. Therefore, this peptide selectively associated with cholesterol-rich lipoproteins and mediated their acute clearance in vivo.

Animals↗
PubMed1992

Sexual differences in lipoprotein composition in a family with dyslipidemic hypertension with premature atheroschlerosis: deficiency of high-density lipoprotein-L and high-density lipoprotein-M "apolipoprotein-I alone" particle.

This article describes a family with a high incidence of premature atherosclerosis and primary hypertriglyceridemia in the women. The lipoprotein composition of this family was investigated with a new methodology that combines gradient ultracentrifugation to isolate lipoprotein subfractions with high-performance liquid chromatography to quantitate apolipoproteins. The major lipoprotein abnormalities that were identified in the hyperlipidemic women in this family were (1) an increased mass of very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) with triglyceriderich VLDL but normal IDL composition; (2) triglyceride-rich low-density lipoprotein (LDL) with normal cholesterol and apolipoprotein B concentrations; (3) a relatively normal total mass of high-density lipoprotein (HDL)-L and HDL-M but with a reduction in the apolipoprotein A-I/A-II ratio and a decrease in the cholesterol to triglyceride ratio; (4) an elevation of HDL-D apolipoprotein A-I. The reduction in the apolipoprotein A-I/A-II ratio was also seen in the hyperlipidemic men and in most of nonhyperlipidemic family members and was the most common lipoprotein abnormality that was identified in this family (9 of 11 family members who were not on lipid-lowering medications were affected). The hypertriglyceridemic women appeared to have an increase in the "A-I + A-II" HDL particles in all subfractions and an increase in the "A-I alone" particles in HDL-D. These increases provided the apparently normal total mass of HDL that was observed in these women. These increases in HDL were not seen in the hypertriglyceridemic men. We conclude that a deficiency of the "A-I alone" particle in HDL-L and HDL-M may contribute to the premature atherosclerosis that was seen in this family and that it appears to precede the appearance of hypertriglyceridemia. The increase in the "A-I + A-II" HDL particles did not appear to provide the same protection as would be expected from "A-I alone" HDL.

Adult↗
PubMed1992

The effect of bezafibrate on very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) composition in type 1 diabetes associated with hypercholesterolaemia or combined hyperlipidaemia.

Lipoprotein composition was examined in type 1 diabetic subjects with hypercholesterolaemia +/- hypertriglyceridaemia during a 3-month double-blind placebo controlled assessment of bezafibrate therapy. The predominant effect was on lipoprotein lipid content. In those with hypercholesterolaemia alone, bezafibrate significantly reduced the cholesterol (particularly esterified cholesterol) and triglyceride content of large very low density lipoprotein (VLDL) (Svedberg flotation units (Sf) 60-400) in comparison to the placebo group (P less than 0.05), and a trend towards a reduction in free and esterified cholesterol within the intermediate density lipoprotein fraction (IDL) (Sf 12-20) was noted. Low density lipoprotein (LDL) composition was unaltered and in general phospholipid and protein concentrations and cholesteryl ester/protein ratios within the lipoprotein fractions were unaffected. Large VLDL cholesterol and triglyceride concentrations in those with combined hyperlipidaemia were significantly decreased following bezafibrate therapy, both in comparison to placebo-treated subjects and to baseline concentrations (P less than 0.05). An additional significant reduction in small VLDL (Sf 20-60) free cholesterol was recorded (P less than 0.05). Average reductions of large and small VLDL protein of 50-56% were not significant because of wide variation in responses. Bezafibrate had no effect on the abnormal composition of IDL and LDL, characteristic of Type 1 diabetes, regardless of whether or not hypertriglyceridaemia was associated with hypercholesterolaemia. Its major action was to lower VLDL lipid concentrations, but it may also reduce the lipid content of intermediate density lipoprotein in Type 1 diabetes.

Adolescent↗
PubMed1982

[Lipoproteins associated with lipoprotein B in human serum low density lipoproteins].

Small amounts of lipoprotein C and lipoprotein D could be observed in low density lipoproteins (1.030-1.055 g/ml), using electroimmunomigration and polyacrylamide gel electrophoresis. Lipoprotein structures containing several apolipoproteins such as lipoprotein (B+C) or (B+D) were not detected in these low density lipoproteins. Lipoproteins C and D could not be separated from lipoprotein B by using gel filtration and affinity chromatography on heparin-Sepharose. Apolipoproteins C-III and D measured by electroimmunoassay are 3.2 +/- 1.2% and 1.15 +/- 0.6%, respectively, of the proteins found in the density range 1.030-1.055 g/ml, so there is, therefore, about 1 mol of apolipoprotein C-III and 0.1 mol of apolipoprotein D per mol of apolipoprotein B.

Apolipoproteins↗
PubMed2003

The very low density lipoprotein (VLDL) receptor--a peripheral lipoprotein receptor for remnant lipoproteins into fatty acid active tissues.

The VLDL (very low density lipoprotein) receptor is a member of the LDL (low density lipoprotein) receptor family. The VLDL receptor binds apolipoprotein (apo) E but not apo B, and is expressed in fatty acid active tissues (heart, muscle, adipose) and macrophages abundantly. Lipoprotein lipase (LPL) modulates the binding of triglyceride (TG)-rich lipoprotein particles to the VLDL receptor. By the unique ligand specificity, VLDL receptor practically appeared to function as IDL (intermediate density lipoprotein) and chylomicron remnant receptor in peripheral tissues in concert with LPL. In contrast to LDL receptor, the VLDL receptor expression is not down regulated by lipoproteins. Recently several possible functions of the VLDL receptor have been reported in lipoprotein metabolism, atherosclerosis, obesity/insulin resistance, cardiac fatty acid metabolism and neuronal migration. The gene therapy of VLDL receptor into the LDL receptor knockout mice liver showed a benefit effect for lipoprotein metabolism and atherosclerosis. Further researches about the VLDL receptor function will be needed in the future.

Animals↗
PubMed1996

Effects of gonadotropin and testosterone treatments on Lipoprotein(a), high density lipoprotein particles, and other lipoprotein levels in male hypogonadism.

It is known that lipoprotein(a) [Lp(a) is an independent risk factor for developing atherosclerosis, whereas the LpA-I particle of high density lipoprotein (HDL) is an antiatherogenic factor. The effects of androgen replacement therapy on lipid and lipoproteins have previously been reported in male hypogonadism. However, no study reported the effect of gonadotropin or testosterone treatment on Lp(a), LpA-I, or LpA-I;A-II levels in make hypogonadism. We, therefore, determined Lp(a), LpA-I, LpA-I:A-II, and other lipoprotein levels before and 3 months after treatment in 22 patients with idiopathic hypogonadotropic hypogonadism (IHH) and in 9 patients with Klinefelter's syndrome. All patients had been previously untreated for androgen deficiency. Plasma FSH, LH, PRL, testosterone (T), estradiol, and dehydroepiandrosterone sulfate levels were also determined before and 3 months after treatment. Patients with IHH were treated with hCG/human menopausal gonadotropin, whereas patients with Klinefelter's syndrome received T treatment. Three months after treatment, mean T levels role to low normal levels in both groups. Triglyceride, LpA-I:A-II, Lp(a), HDL cholesterol, HDL3 cholesterol, and apolipoprotein (apo) A-I concentrations did not change significantly after treatment, whereas total cholesterol, low density lipoprotein cholesterol, LpA-I, and HDL2 concentrations were significantly increased 3 months after treatment in both groups. The apo B concentration significantly increased in patients with klinefelter's syndrome, whereas no change was observed in the IHH group. Lp(a) concentrations were not related to all hormonal and clinical parameters in both groups. LpA-I concentrations were significantly and negatively correlated with free T (r = -0.80; P = 0.010) in patients with Klinefelter's syndrome and were not correlated with all hormonal and clinical parameters in the IHH group. The LpA-I:A-II concentration was only correlated with body mass index (r = -0.83; P = 0.005) in patients with Klinefelter's syndrome, whereas it was correlated negatively with dehydroepiandrosterone sulfate (r = -0.57; P = 0.005) in the IHH group.2 Overall, our study demonstrates that gonadotropin or T treatment has a complex effect on lipids and lipoproteins. This complexity will be resolved when sufficient large scale androgen treatment data are available for assessment of the long term outcome of androgen treatment. The increases in total cholesterol and low density lipoprotein cholesterol concentrations after treatments are the adverse effects of these treatments, whereas the increases in HDL2 and LpA-I concentrations and the lack of changes in Lp(a) are the beneficial effects. Gonadotropin or T treatment did not modify the Lp(a) concentration, indicating that it is not affected by the hormonal milieu in male hypogonadism. Our study also showed that LpA-I, but not LpA-I:A-II, particles could be modified by androgen replacement therapy.

Adult↗
PubMed1979

Suppression of 3-hydroxy-3-methylglutaryl-CoA reductase by low density lipoproteins produced in vitro by lipoprotein lipase action on nonsuppressive very low density lipoproteins.

Very low density lipoproteins (VLDL), Sf60 to 400, from normolipemic individuals do not suppress 3-hydroxy-3-methylglutaryl-CoA reductase activity in cultured normal human fibroblasts at concentrations 20-fold higher than those of low density lipoproteins (LDL) that give total suppression. To determine if these VLDL contain all of the structural elements necessary for receptor-mediated suppression, they were converted in vitro with bovine milk lipoprotein lipase to low density lipoproteins. These LDL-like lipoproteins were as effective in suppression as LDL isolated directly from plasma, with half-maximal and complete suppression at 1 and 4 microgram of cholesterol ml-1. Neither native LDL nor LDL produced in vitro suppressed receptor-negative fibroblasts. We conclude that action of lipoprotein lipase on VLDL leads to a rearrangement of lipoprotein components that permits interaction of LDL produced in vitro with the LDL-specific cell surface receptor of fibroblasts and subsequent suppression of 3-hydroxy-3-methylglutaryl-CoA reductase.

Cells, Cultured↗
PubMed1992

Complete down-regulation of low-density-lipoprotein-receptor activity in the human hepatoma cell line Hep G2 by beta-migrating very-low-density lipoprotein and non-lipoprotein cholesterol. Different cellular regulatory pools of cholesterol.

Regulation of low-density-lipoprotein-receptor activity by low-density lipoprotein (LDL), cholesteryl-ester-rich beta-migrating very-low-density lipoprotein (beta-VLDL) and non-lipoprotein cholesterol was investigated in the human hepatoma cell line Hep G2. Competition studies indicate that LDL and beta-VLDL are bound to the same recognition site, tentatively the LDL receptor. The regulatory response of the LDL receptor upon prolonged incubation with LDL or beta-VLDL was, however, markedly different. 22 h preincubation of Hep G2 cells with excess LDL caused a partial down regulation to 31% of the initial level of the high-affinity association of LDL and 26% of the high-affinity degradation of LDL, while with beta-VLDL a complete down regulation of the LDL-receptor activity is observed. Preincubation of Hep G2 cells with beta-VLDL for 22 h led to a fourfold increase in intracellular cholesterol esters and a twofold increase in acyl-coA:cholesterol acyltransferase activity. With LDL, the amount of intracellular cholesterol esters is increased 1.6-fold. The more effective down regulation of LDL receptors by beta-VLDL as compared to LDL can be explained by the more effective intracellular cholesterol delivery with beta-VLDL than with LDL. Preincubation of Hep G2 cells for 22 h with acetylated LDL hardly influenced the LDL-receptor activity. Non-lipoprotein cholesterol, however, caused a complete down regulation of LDL-receptor activity at even lower extracellular cholesterol concentrations than with beta-VLDL. The complete down regulation of LDL receptors by non-lipoprotein cholesterol is not accompanied by a significant increase in acyl-coA:cholesterol acyltransferase activity, while the intracellular cholesterol ester concentration is only increased 1.6-fold. It is suggested that the effectiveness of non-lipoprotein cholesterol to regulate LDL receptors is caused by its efficiency to reach the sterol regulatory site. The inability of LDL to down regulate its receptor completely can thus be explained by the inability of LDL to deliver cholesterol adequately at the intracellular regulatory site of the LDL receptor. The observed complete down regulation of the LDL receptor by beta-VLDL may be responsible for the cholesterol-rich-diet induced, complete down regulation of LDL-receptor-mediated clearance of LDL in vivo.

Binding, Competitive↗
PubMed1998

Liver-specific overexpression of scavenger receptor BI decreases levels of very low density lipoprotein ApoB, low density lipoprotein ApoB, and high density lipoprotein in transgenic mice.

Scavenger receptor BI (SR-BI) is known to mediate the selective uptake of high density lipoprotein (HDL) cholesteryl ester (CE) in liver and steroidogenic tissues. To evaluate the role of SR-BI in plasma lipoprotein metabolism, we have generated transgenic mice with liver-specific overexpression of murine SR-BI. On a chow diet SR-BI transgenic (SR-BI Tg) mice have decreased HDL-CE, apoA-I, and apoA-II levels; plasma triglycerides, low density lipoprotein (LDL) cholesterol, and very low density lipoprotein (VLDL) and LDL apoB were also decreased, compared with control mice. Turnover studies using non-degradable CE and protein labels showed markedly increased total and selective uptake of HDL-CE in the liver and increased HDL protein catabolism in both liver and kidney. To evaluate the changes in apoB further, mice were challenged with high fat, high cholesterol diets. In SR-BI Tg mice plasma apoB levels were only 3-15% of control levels, and the dietary increase in VLDL and LDL apoB was virtually abolished. These studies show that steady state overexpression of hepatic SR-BI reduces HDL levels and increases reverse cholesterol transport. They also indicate that SR-BI can play a role in the metabolism of apoB-containing lipoproteins. The dual effects of increased reverse cholesterol transport and lowering of apoB-containing lipoproteins that result from hepatic SR-BI overexpression could have anti-atherogenic consequences.

Animals↗
PubMed1994

The carboxyl-terminal domain of lipoprotein lipase binds to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and mediates binding of normal very low density lipoproteins to LRP.

Lipoprotein lipase (LPL) binds with high affinity to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and promotes binding, uptake, and degradation of normal triglyceride-rich lipoproteins in a process mediated by LRP (Chappell, D. A., Fry, G. L., Naknitx, M.A., Muhonen, L. E., Pladet, M. W., Iverius, P-H., and Strickland, D. K. (1993) J. Biol. Chem. 268, 14168-14175). To localize the portion of LPL that is responsible for interacting with LRP, fragments of LPL were expressed in bacteria. A fragment of human LPL containing the COOH-terminal domain (residues 313-448, designated LPLC) which lacks the catalytic site was able to bind to LRP. Purified LRP bound specifically to microtiter wells coated with LPL or LPLC with KD values of 2.8 and 5 nM, respectively. The effects of several mutations of LPLC were tested. Mutation of Lys407 to Ala reduced the affinity of LPLC for LRP by approximately 10-fold. Like native LPL, LPLC prevented the binding of activated alpha 2-macroglobulin and the 39-kDa receptor-associated protein to LRP and inhibited the internalization and degradation of activated alpha 2-macroglobulin and receptor-associated protein in cultured fibroblasts. LPLC also bound to 125I-labeled human normal triglyceride-rich lipoproteins and promoted their binding to purified LRP and to cultured cells. Mutation of Trp393 and Trp394 to Ala completely abolished the ability of LPLC to bind to lipoproteins, but had little effect on its interaction with LRP. These data indicate that the COOH-terminal domain of LPL may function both in binding lipoproteins and mediating their interaction with LRP.

Amino Acid Sequence↗