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PubMed2000

The effects of isolated lipoproteins and triglyceride, combined oxidized low density lipoprotein (LDL) plus triglyceride, and combined oxidized LDL plus high density lipoprotein on the contractile and relaxation response of rabbit cavernous smooth muscle.

The aim of this study was to investigate the effects of isolated lipoproteins and triglyceride (TG), and the effects of combined oxidized low density lipoprotein (LDL) plus TG and the combined oxidized LDL plus high density lipoprotein (HDL) on the contractility and relaxation response of rabbit cavernous smooth muscle. Cavernous muscle strips from New Zealand White rabbits were studied in organ chambers for isometric tension measurement. The strips were exposed to HDL, LDL, oxidized LDL, TG, combined oxidized LDL plus TG and combined oxidized LDL plus HDL for 30 min. Both HDL and LDL did not affect contraction and relaxation responses of the cavernous muscles. The oxidized LDL did not affect norepinephrine (NE)-induced contractility of the strips, but significantly (p < 0.05) decreased the relaxation response to endothelium-dependent agonist, acetylcholine (Ach). Non-specific NO synthase inhibitor (L-NAME) completely inhibited the relaxation response to Ach, and L-arginine partially improved the diminished relaxation. TG did not significantly change the relaxation responses to Ach, but decreased the contractility of cavernous muscle to NE. Neither the combined oxidized LDL plus TG nor oxidized LDL plus HDL had significant synergistic or detoxication effects on the contractility and relaxation responses. In conclusion, oxidized LDL may have acute toxic effects on the endothelium-dependent, NO-mediated relaxation, but not on the contractility, of rabbit cavernous smooth muscle. TG may decrease contractility of the cavernous muscle. There may be neither synergistic nor detoxication effects on the contractility and relaxation response when TG or HDL is added to the oxidized LDL.

Animals↗
PubMed2001

Adenovirus-mediated rescue of lipoprotein lipase-deficient mice. Lipolysis of triglyceride-rich lipoproteins is essential for high density lipoprotein maturation in mice.

Lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of triglycerides and the subsequent uptake of free fatty acids in extrahepatic tissues. Deficiency of LPL in humans (Type I hyperlipoproteinemia) is associated with massive chylomicronemia, low high density lipoprotein (HDL) cholesterol levels, and recurrent attacks of pancreatitis when not controlled by a strict diet. In contrast to humans, homozygous LPL knock-out mice (L0) do not survive suckling and die between 18 and 24 h after birth. In this study, an adenovirus-based protocol was utilized for the transient expression of LPL during the suckling period in an effort to rescue L0 mice. After a single intraperitoneal injection of 5x10(9) plaque-forming units of LPL-expressing virus immediately after birth, more than 90% of L0 mice survived the first days of life. 3% of L0 mice survived the entire suckling period and lived for up to 20 months, although LPL activity in mouse tissues and postheparin plasma was undetectable in all animals after 6 weeks of age. Adult LPL-deficient mice were smaller than their littermates until 2-3 months of age and exhibited very high triglyceride levels in the fed (4997 +/- 1102 versus 113.4 +/- 18.7 mg/dl) and fasted state (2007 +/- 375 versus 65.5 +/- 7.4 mg/dl). Plasma total cholesterol levels, free fatty acids, and ketone bodies were elevated in L0 mice, whereas plasma glucose was normal. Most strikingly, L0 mice lacked apoA-I-containing prebeta-HDL particles as well as mature HDL resulting in undetectable HDL cholesterol and HDL-apoA-I levels. HDL deficiency in plasma was evident despite normal apoA-I mRNA levels in the liver and normal apoA-I protein levels in plasma, which were predominantly found in the chylomicron fraction. The absence of prebeta-HDL and mature HDL particles supports the concept that the lipolysis of triglyceride-rich lipoproteins is an essential step for HDL maturation.

Adenoviridae↗
PubMed1999

Linkage of low-density lipoprotein size to the lipoprotein lipase gene in heterozygous lipoprotein lipase deficiency.

Small low-density lipoprotein (LDL) particles are a genetically influenced coronary disease risk factor. Lipoprotein lipase (LpL) is a rate-limiting enzyme in the formation of LDL particles. The current study examined genetic linkage of LDL particle size to the LpL gene in five families with structural mutations in the LpL gene. LDL particle size was smaller among the heterozygous subjects, compared with controls. Among heterozygous subjects, 44% were classified as affected by LDL subclass phenotype B, compared with 8% of normal family members. Plasma triglyceride levels were significantly higher, and high-density lipoprotein cholesterol (HDL-C) levels were lower, in heterozygous subjects, compared with normal subjects, after age and sex adjustment. A highly significant LOD score of 6.24 at straight theta=0 was obtained for linkage of LDL particle size to the LpL gene, after adjustment of LDL particle size for within-genotype variance resulting from triglyceride and HDL-C. Failure to adjust for this variance led to only a modest positive LOD score of 1.54 at straight theta=0. Classifying small LDL particles as a qualitative trait (LDL subclass phenotype B) provided only suggestive evidence for linkage to the LpL gene (LOD=1. 65 at straight theta=0). Thus, use of the quantitative trait adjusted for within-genotype variance, resulting from physiologic covariates, was crucial for detection of significant evidence of linkage in this study. These results indicate that heterozygous LpL deficiency may be one cause of small LDL particles and may provide a potential mechanism for the increase in coronary disease seen in heterozygous LpL deficiency. This study also demonstrates a successful strategy of genotypic specific adjustment of complex traits in mapping a quantitative trait locus.

Adolescent↗
PubMed1987

Distinction in the mode of receptor-mediated endocytosis between high density lipoprotein and acetylated high density lipoprotein: evidence for high density lipoprotein receptor-mediated cholesterol transfer.

The interactions of high density lipoprotein (HDL) and acetylated high density lipoprotein (acetyl-HDL) with isolated rat sinusoidal liver cells have been investigated. Cellular binding of 125I-acetyl-HDL at 0 degrees C demonstrated the presence of a specific, saturable membrane-associated receptor. This receptor was affected neither by formaldehyde-treated albumin nor by low density lipoprotein modified either by acetylation or malondialdehyde, ligands known to undergo receptor-mediated endocytosis by the cells, indicating that the receptor for acetyl-HDL constitutes a distinct class among the scavenger receptors for chemically modified proteins. Parallel binding experiments using 125I-HDL also revealed the presence on these cells of a receptor for unmodified HDL. The ligand specificities of these two receptors were similar to each other except that the acetyl-HDL receptor was sensitive to polyanions such as dextran sulfate and fucoidin. Interaction of HDL with the cells at 37 degrees C was totally different from that of acetyl-HDL. Cellular binding of HDL was not accompanied by subsequent intracellular degradation of its apoprotein moiety, whereas its cholesterol moiety was significantly transferred to the cells. In contrast, acetyl-HDL was endocytosed and underwent lysosomal degradation as a holoparticle. This shift in receptor-recognition from the HDL receptor to the acetyl-HDL receptor was accomplished by acetylation of approximately 8% of the total lysine residues of HDL apoprotein. This unique difference in endocytic behavior between HDL and acetyl-HDL suggests a potential link of the HDL receptor to HDL-mediated cholesterol transfer in sinusoidal liver cells.

Acetylation↗
PubMed2004

Subclasses of low-density lipoprotein and very low-density lipoprotein in familial combined hyperlipidemia: relationship to multiple lipoprotein phenotype.

OBJECTIVE: The present study addresses the presence of distinct metabolic phenotypes in familial combined hyperlipidemia (FCHL) in relation to small dense low-density lipoprotein (sd LDL) and very low-density lipoprotein (VLDL) subclasses. METHODS AND RESULTS: Hyperlipidemic FCHL relatives (n=72) were analyzed for LDL size by gradient gel electrophoresis. Pattern B LDL (sd LDL, particle size <258 A) and pattern A LDL (buoyant LDL, particle size > or =258 A) were defined. Analyses showed bimodal distribution of LDL size associated with distinct phenotypes. Subjects with predominantly large, buoyant LDL showed a hypercholesterolemic phenotype and the highest apo B levels. Subjects with predominantly sd LDL showed a hypertriglyceridemic, low high-density lipoprotein (HDL) cholesterol phenotype, with moderately elevated apoB, total cholesterol level, and LDL cholesterol level. Subjects with both buoyant LDL and sd LDL (pattern AB, n=7) showed an intermediate phenotype, with high normal plasma triglycerides. VLDL subfraction analysis showed that the sd LDL phenotype was associated with a 10-times higher number of VLDL1 particles of relatively lower apo AI and apo E content, as well as smaller VLDL2 particles, in combination with increased plasma insulin concentration in comparison to pattern A. CONCLUSIONS: The present observations underscore the importance of the VLDL triglyceride metabolic pathway in FCHL as an important determinant of the phenotypic heterogeneity of the disorder.

Adult↗
PubMed2002

The relationship among apolipoprotein(a) polymorphisms, the low-density lipoprotein receptor-related protein, and the very low density lipoprotein receptor genes, and plasma lipoprotein(A) concentration in the Czech population.

Increased plasma concentration of lipoprotein(a) [Lp(a)] is an established independent risk factor for coronary artery disease (CAD), which is strongly genetically determined. This study was designed to investigate the relationship between the K-IV and (TTTTA)n apolipoprotein(a) [apo(a), protein; APOA, gene] polymorphisms, as well as the C766T low-density lipoprotein receptor-related protein (LRP) and the (CGG)n very low density lipoprotein receptor (VLDLR) polymorphisms on the one hand, and plasma Lp(a) levels in Czech subjects who underwent coronary angiography on the other hand. The lengths of the alleles of the APOA K-IV and (TTTTA)n polymorphisms were strongly inversely correlated with plasma Lp(a) levels in univariate analysis (r = -0.41, p < 10(-4) and r = -0.20, p < 0.01, respectively). Multivariate analysis revealed significant associations between the APOA polymorphisms studied and plasma Lp(a) levels in subjects expressing only one APOA K-IV allele (p < 10(-6) for K-IV and p < 0.001 for TTTTA). In subjects expressing both APOA K-IV alleles, the multivariate analysis revealed that only the APOA K-IV alleles were inversely correlated with plasma Lp(a) levels (p < 0.001). Associations between both the LRP and VLDLR gene polymorphisms and plasma Lp(a) levels were only of borderline significance (p < 0.06 and p < 0.07, respectively) and were not confirmed in multivariate analysis. In conclusion, both APOA length polymorphisms significantly influenced plasma Lp(a) concentration in the Czech population studied, and this circumstance could explain the association in this population observed earlier between APOA (TTTTA)n polymorphism and CAD (Benes et al. 2000). Only a minor role in the regulation of plasma Lp(a) levels is suggested for the C766T LRP and the (CGG)n VLDLR polymorphisms.

Alleles↗
PubMed1991

Comparison of plasma clearance of low density lipoprotein with beta-very low density lipoprotein or acetoacetylated low density lipoprotein in cholesterol-fed rabbits.

The plasma clearance and tissue distribution of radioiodinated low-density lipoprotein (LDL), beta-very low density lipoprotein (beta-VLDL), and acetoacetylated LDL were studied in cholesterol-fed rabbits. Radioiodinated LDL ([125I]LDL) was cleared more slowly than either [125I]beta-VLDL or acetoacetylated-[125I]LDL and its fractional catabolic rate was one-half that of [125I]beta-VLDL and one-ninth that of acetoacetylated-[125I]LDL. Forty-eight hours after the injection of the labeled lipoproteins, the hepatic uptake was the greatest among the organs evaluated with the uptake of [125I]LDL being one-third that of either [125I]beta-VLDL or acetoacetylated-[125I]LDL. The reduction in the hepatic uptake of LDL due to a down-regulation of the receptors would account for this retarded plasma clearance.

Animals↗
PubMed1978

Metabolic heterogeneity in the formation of low density lipoprotein from very low density lipoprotein in the rat: evidence for the independent production of a low density lipoprotein subfraction.

The formation of low density lipoprotein (LDL) from very low density lipoprotein (VLDL) was studied after injecting 14C-radiomethylated or 125I-radioiodinated VLDL into rats. VLDL and LDL B apoprotein specific radioactivity time curves were obtained after tetramethylurea extraction of the lipoproteins. In all experiments, the specific activity of LDL B apoprotein did not intercept the VLDL curve at maximal heights, suggesting that not all LDL B apoprotein is derived from VLDL B apoprotein. Further subfractionation of LDL into the Sf 12-20, 5-12, and 0-5 ranges showed that most (65%) LDL B apoprotein was present in the Sf 0-5 fraction and that only a small proportion (6-15%) of this fraction was derived from VLDL. However, the curves obtained for the Sf 12-20 and 5-12 subfractions were consistent with a precursor-product relationship in which all of these fractions were derived entirely from VLDL catabolism. These results contrasted strikingly with similar data obtained for normal humans in which all LDL is derived from VLDL. In the rat, it appears that most of the B apoprotein in the Sf 0-5 range, which contains 65% of the total LDL B apoprotein, enters the plasma independently of VLDL secretion.

Animals↗
PubMed1993

High density lipoprotein and low density lipoprotein attenuate the inhibitory effects of oxidized low density lipoprotein on endothelium-dependent arterial relaxation.

We have recently reported that oxidized low density lipoprotein (ox-LDL) inhibits endothelium-dependent arterial relaxation through its increased lysophosphatidylcholine (LPC). In this study we examined whether high density lipoprotein (HDL) as well as native low density lipoprotein have any effects on the inhibition of endothelium-dependent relaxation by ox-LDL in isolated strips of rabbit thoracic aorta. Both LDL and HDL were isolated from normal human plasma and LDL was oxidized by exposure to copper. Preincubation of arterial strips with ox-LDL (0.1-0.5 mg protein/ml) inhibited endothelium-dependent relaxation to acetylcholine (ACh) in a concentration-dependent manner. HDL (1 mg protein/ml) by itself had no effect on the relaxation to ACh. In the presence of HDL, the inhibition by ox-LDL was markedly reduced. In addition, native LDL also attenuated the inhibition of endothelium-dependent relaxation by ox-LDL. Thus, HDL and native LDL may have salutary effects against the impairment of endothelium-mediated vasodilation in atherosclerotic arteries.

Acetylcholine↗
PubMed1998

Evolving lipoprotein risk factors: lipoprotein(a) and oxidized low-density lipoprotein.

Cardiovascular disease is the leading cause of morbidity and mortality in Westernized populations. Evolving lipoprotein risk factors include LDL oxidation and lipoprotein(a) [lp(a)]. Several lines of evidence support a role for oxidatively modified LDL in atherogenesis and its in vivo existence. There are both direct and indirect measures of oxidative stress. The most relevant direct measure of lipid peroxidation is urinary F2 isoprostanes. The most common indirect measure of LDL oxidation is quantifying the lag phase of copper-catalyzed LDL oxidation by assaying conjugated diene formation. Lp(a) is increased in patients with cardiovascular and cerebrovascular disease. However, not all prospective studies have confirmed a positive relationship between Lp(a) and cardiovascular events. Lp(a) appears to present three major problems: standardization of the assay, establishing its role in atherogenesis, and the lack of an effective therapy that can substantially lower Lp(a) concentrations. Thus, at the present time, Lp(a) concentrations should not be recommended for the general population but be reserved for patients with coronary artery disease without established risk factors, young patients with coronary artery disease or cerebrovascular disease, or a family history of premature atherosclerosis and family members of an index patient with increased concentrations of Lp(a). Although both LDL oxidation and Lp(a) are evolving risk factors for cardiovascular disease, more data are needed before they become part of the established lipoprotein repertoire.

Animals↗
PubMed1995

Comparison of gemfibrozil versus simvastatin in familial combined hyperlipidemia and effects on apolipoprotein-B-containing lipoproteins, low-density lipoprotein subfraction profile, and low-density lipoprotein oxidizability.

We evaluated in a double-blind, placebo-controlled, randomized trial of 45 well-defined patients with familial combined hyperlipidemia, the effect of gemfibrozil (1,200 mg/day) or simvastatin (20 mg/day) on apolipoprotein-B (apo-B)-containing lipoproteins, low-density lipoprotein (LDL) subfraction profile, and LDL oxidizability. Although both drugs reduced plasma cholesterol and triglyceride concentrations, gemfibrozil reduced plasma triglycerides more effectively and simvastatin reduced plasma cholesterol more effectively. LDL cholesterol was reduced with simvastatin. With both drugs, total serum apo-B concentration decreased. With gemfibrozil, this was due to an exclusive reduction (-46%) of very low/intermediate-density lipoprotein (VLDL + IDL) apo-B, whereas simvastatin decreased apo-B in both VLDL + IDL and LDL (34% and 15%, respectively). Initially, a dense LDL subfraction profile was present in all patients. The decrease in LDL cholesterol with simvastatin was due to a decrease in all isolated LDL subfractions except LDL2; gemfibrozil increased LDL1 and LDL2 cholesterol (p = 0.001) and reduced LDL4 cholesterol, resulting in a more buoyant LDL subfraction profile compared with simvastatin. In both groups, a predominance of small dense LDL remained despite therapy. LDL fatty acid composition showed a shift from oleic acid to linoleic acid after gemfibrozil; arachidonic acid increased after simvastatin. Vitamin E was lower after gemfibrozil. In the measurements of LDL oxidation, only the oxidation rate was significantly reduced with simvastatin. Thus, quantitative and qualitative changes of LDL cholesterol had only a small effect on total in vitro LDL oxidizability in this population with familial combined hyperlipidemia.

Adult↗
PubMed1995

Limited discriminant value of lipoprotein AI, lipoprotein Lp(a) and other lipoprotein particles in patients with and without early onset ischaemic heart disease.

AIMS: To assess whether the ability of lipoprotein related variables to discriminate between individuals with or without premature clinical ischaemic heart disease (IHD) was improved using data on high density lipoprotein-lipoprotein AI (HDL-LpAI) fractions, alone or in combination with data on Lp(a). METHODS: Lipid and apolipoprotein concentrations were measured in 26 middle-aged men (mean age 50.3 years) with early onset IHD and coronary artery bypass grafting prior to sampling, and in 26 matched lipaemic and 26 normolipaemic asymptomatic controls. RESULTS: Triglyceride and Lp(a) concentrations were higher, while HDL cholesterol and apolipoprotein A-I (apoA-I) concentrations were lower in patients than in controls. LpAI concentrations were also lower in IHD patients and were correlated with HDL and apoA-I in both IHD and control groups. Lp(a) was not correlated with any other lipid or apolipoprotein measured in either patients or controls. Univariate discriminant function analysis showed that the proportion correctly classified as patients or controls was marginally greater using LpAI concentrations as the discriminator, which was not increased in combination with Lp(a). Serum triglycerides, HDL cholesterol, apoA-I and Lp(a) alone all had similar, but weaker, discriminant power, which increased in various combinations with LpAI. CONCLUSIONS: LpAI particle measurement may be useful in research to define mechanisms of cardiovascular protection by HDL but the discriminating power for IHD was only marginally superior to measuring total apoA-I or Lp(a) concentrations. Little further advantage arose through combining LpAI data with other variables.

Adult↗
PubMed1996

Structure-function relationship of lipoprotein lipase-mediated enhancement of very low density lipoprotein binding and catabolism by the low density lipoprotein receptor. Functional importance of a properly folded surface loop covering the catalytic center.

We examined the structure-function relationship of human lipoprotein lipase (hLPL) in its ability to enhance the binding and catabolism of very low density lipoproteins (VLDL) in COS cells. Untransfected COS cells did not bind to or catabolize normal VLDL. Expression of wild-type hLPL by transient transfection enhanced binding, uptake, and degradation of the VLDL (a property of LPL that we call bridge function). Heparin pretreatment and a monoclonal antibody ID7 that blocks LDL receptor-binding domain of apoE both inhibited binding, and apoE2/E2 VLDL from a Type III hyperlipidemic subject did not bind. However, LDL did not reduce 125I-VLDL binding to the hLPL-expressing cells, whereas rabbit beta-VLDL was an effective competitor. By contrast, LDL reduced uptake and degradation of 125I-VLDL to the same extent as excess unlabeled VLDL or beta-VLDL. These data suggest that binding occurs by direct interaction of VLDL with LPL but the subsequent catabolism of the VLDL is mediated by the LDL receptor. Mutant hLPLs that were catalytically inactive, S132A, S132D, as well as the partially active mutant, S251T, and S172G, gave normal enhancement of VLDL binding and catabolism, whereas the partially active mutant S172D had markedly impaired capacity for the process; thus, there is no correlation between bridge function and lipolytic activity. A naturally occurring genetic variant hLPL, S447-->Ter, has normal bridge function. The catalytic center of LPL is covered by a 21-amino acid loop that must be repositioned before a lipid substrate can gain access to the active site for catalysis. We studied three hLPL loop mutants (LPL-cH, an enzymatically active mutant with the loop replaced by a hepatic lipase loop; LPL-cP, an enzymatically inactive mutant with the loop replaced by a pancreatic lipase loop; and C216S/C239S, an enzymatically inactive mutant with the pair of Cys residues delimiting the loop substituted by Ser residues) and a control double Cys mutant, C418S/C438S. Two of the loop mutants (LPL-cH and LPL-cP) and the control double Cys mutant C418S/C438S gave normal enhancement of VLDL binding and catabolism, whereas the third loop mutant, C216S/C239S, was completely inactive. We conclude that although catalytic activity and the actual primary sequence of the loop of LPL are relatively unimportant (wild-type LPL loop and pancreatic lipase loops have little sequence similarity), the intact folding of the loop, flanked by disulfide bonds, must be maintained for LPL to express its bridge function.

Animals↗
PubMed1995

Severe hypertriglyceridemia, reduced high density lipoprotein, and neonatal death in lipoprotein lipase knockout mice. Mild hypertriglyceridemia with impaired very low density lipoprotein clearance in heterozygotes.

Lipoprotein lipase (LPL)-deficient mice have been created by gene targeting in embryonic stem cells. At birth, homozygous knockout pups have threefold higher triglycerides and sevenfold higher VLDL cholesterol levels than controls. When permitted to suckle, LPL-deficient mice become pale, then cyanotic, and finally die at approximately 18 h of age. Before death, triglyceride levels are severely elevated (15,087 +/- 3,805 vs 188 +/- 71 mg/dl in controls). Capillaries in tissues of homozygous knockout mice are engorged with chylomicrons. This is especially significant in the lung where marginated chylomicrons prevent red cell contact with the endothelium, a phenomenon which is presumably the cause of cyanosis and death in these mice. Homozygous knockout mice also have diminished adipose tissue stores as well as decreased intracellular fat droplets. By crossbreeding with transgenic mice expressing human LPL driven by a muscle-specific promoter, mouse lines were generated that express LPL exclusively in muscle but not in any other tissue. This tissue-specific LPL expression rescued the LPL knockout mice and normalized their lipoprotein pattern. This supports the contention that hypertriglyceridemia caused the death of these mice and that LPL expression in a single tissue was sufficient for rescue. Heterozygous LPL knockout mice survive to adulthood and have mild hypertriglyceridemia, with 1.5-2-fold elevated triglyceride levels compared with controls in both the fed and fasted states on chow, Western-type, or 10% sucrose diets. In vivo turnover studies revealed that heterozygous knockout mice had impaired VLDL clearance (fractional catabolic rate) but no increase in transport rate. In summary, total LPL deficiency in the mouse prevents triglyceride removal from plasma, causing death in the neonatal period, and expression of LPL in a single tissue alleviates this problem. Furthermore, half-normal levels of LPL cause a decrease in VLDL fractional catabolic rate and mild hypertriglyceridemia, implying that partial LPL deficiency has physiological consequences.

Adipose Tissue↗
PubMedDate not supplied

Cholesterol esterification rates in very low density lipoprotein- and low density lipoprotein-depleted plasma. Relation to high density lipoprotein subspecies, sex, hyperlipidemia, and coronary artery disease.

The fractional rate of cholesterol esterification in very low density lipoprotein- and low density lipoprotein-depleted plasma (FERHDL) was studied in normolipidemic subjects and in individuals with hyperlipidemia and proven coronary artery disease (CAD). The FERHDL was significantly higher than the FER in whole plasma and was significantly higher in normal men than in normal women. In addition, men and women with primary hyperlipidemia had significantly higher FERHDL values relative to their sex-matched controls. The most significant increases in FERHDL values, however, were observed in individuals with CAD. In all patient groups, FERHDL was positively correlated with plasma triglyceride concentration. In addition, FERHDL was negatively related to plasma high density lipoprotein (HDL) cholesterol concentration in all groups except in men with CAD and in normolipidemic women. The gradient gel electrophoretic pattern of HDL from individuals with either low or high FERHDL values indicated an inverse relation between this activity and the relative amount of HDL2b particles. FERHDL likely reflects the metabolic properties of the heterogeneous population of HDL particles in the plasma and may be a function of the relative content of larger and smaller HDL particles. It appears to be a sensitive and reliable functional measure of the particle size distribution in the HDL pool and one of potential clinical value in the assessment of risk for CAD.

Adult↗
PubMed1987

Studies on lipoprotein and adrenal steroidogenesis: II. Utilization of low density lipoprotein- and high density lipoprotein-cholesterol for steroid production in functioning human adrenocortical adenoma cells in culture.

We examined the utilization of human low density lipoprotein (LDL)- and high density lipoprotein (HDL)-cholesterol for steroid production in primary monolayer culture cells from adenomas of primary aldosteronism and Cushing's syndrome and an adrenal of nodular hyperplasia of Cushing's syndrome. We compared the data obtained with findings in the case of cultured normal human adrenocortical cells. In the presence of 10(-7) M adrenocorticotropin (ACTH), the addition of either LDL or HDL to the culture medium at a cholesterol concentration of 100 micrograms/ml led to a significant increase in the daily secretion rates of cortisol, dehydroepiandrosterone sulfate (DHEA-S) and aldosterone in the adenoma and nodular hyperplasia cells, as in the normal cells. Although LDL greatly increased the secretion of steroid hormones, no significant difference in steroid secretion following the treatments with LDL and HDL were observed in these cultured cells. The contribution of endogenous cholesterol to steroid production was also high, thereby indicating that the neoplastic transformation did not have untoward effects. Cells from adenomas of primary aldosteronism secreted not only aldosterone, but also cortisol and DHEA-S. The daily secretion rates of these steroids were markedly increased when ACTH was added to the medium. With prolonged exposure to ACTH, however, the rate of aldosterone secretion showed a gradual decrease with the incubation time. This decrease might be due to the impaired conversion of corticosterone to 18-hydroxycorticosterone. In case of adenomas in patients with Cushing's syndrome, the secretion of steroid hormones varied in quantity and quality, depending on the type of plasma cortisol response to the rapid ACTH test in vivo, thereby suggesting that the adrenocortical adenoma of Cushing's syndrome might be divided into two subtypes. These results indicate that human functioning adrenocortical adenoma cells utilize plasma lipoproteins as a source of cholesterol for steroidogenesis during the prolonged stimulation of steroid secretion.

Adenoma↗
PubMed1995

The affinity of low-density lipoproteins and of very-low-density lipoprotein remnants for the low-density lipoprotein receptor in homozygous familial defective apolipoprotein B-100.

We have identified two familial defective apo B-100 (FDB) homozygotes by DNA sequencing and have measured affinity of low-density lipoproteins (LDL) and very-low-density lipoprotein (VLDL) remnants for the LDL receptor in vitro. The patients were a 66-year-old man with coronary heart disease (plasma cholesterol level, 9.5 mmol/l before treatment) and his 69-year-old sister, without signs of cardiovascular disease (plasma cholesterol, 12.0 mmol/l before treatment). In both patients, treatment with statins caused a marked fall in plasma cholesterol level. Binding affinity of LDL from the two patients was 10%-20% of normal at 4 degrees C and 37 degrees C. Binding affinity of VLDL remnants was normal. We conclude that (1) residual affinity of LDL in homozygous FDB is high enough to permit significant catabolism via the LDL-receptor pathway, and (2) normal affinity of VLDL remnants permits normal hepatic clearance of precursors of LDL and increased clearance of LDL precursors when receptor activity is stimulated by statins. Residual affinity of LDL and normal affinity of remnants could explain why expression of the FDB mutation is generally milder than that of LDL receptor mutations causing familial hypercholesterolaemia.

Aged↗
PubMed1993

Smoking and plasma lipoproteins in man: effects on low density lipoprotein cholesterol levels and high density lipoprotein subfraction distribution.

In a survey of a healthy population (n = 197), LDL cholesterol, plasma triglycerides and VLDL triglycerides were found to be substantially increased and plasma HDL cholesterol decreased in smokers. The lipid-associated atherogenic risk in smokers as assessed by the LDL/HDL ratio was significantly higher [2.89 (SD 1.18, n = 63)] than in non-smokers [2.38 (SD 0.98, n = 86) P < 0.01]. The lower HDL level found in smokers was explained by a lower HDL-2 subfraction as determined by analytical ultracentrifugation. HDL 2b, 2a and 3a, measured by gradient gel electrophoresis, were all lower in the smokers but this was only significant for HDL 2a. Smoking had no effect on Lp(a) levels. HDL cholesterol and HDL-2 were strongly negatively correlated whereas LDL cholesterol and LDL/HDL ratio were strongly positively correlated with the plasma triglyceride concentration. There was a small but significant reduction in plasma CETP activity [non-smokers 49% t/microliter (SD 17, n = 90), smokers 43% t/microliter (SD 17, n = 66) P < 0.05] but CETP activity was not correlated with any measure of HDL in this population. Smoking was found to be an important independent contributor to the variation in plasma triglyceride, HDL, HDL-2 and LDL/HDL ratio. After correcting for sex, age, BMI, alcohol consumption, oral contraceptive use and plasma triglycerides smoking was still found to be significantly associated with HDL and the LDL/HDL ratio. Upon adjustment for covariant factors the mean differences between smokers and non-smokers for HDL cholesterol, HDL-2 and LDL/HDL were 0.15 mM, 16 mg dl-1 and 0.39 respectively. There appeared to be important sex differences in the influence of smoking on plasma lipoproteins. In women the main impact of smoking was on triglyceride levels and they in turn affected LDL and HDL. In contrast, in men, smoking had little impact on triglycerides and affected HDL more directly. We conclude that smoking cigarettes has an important effect on plasma lipoprotein metabolism through multiple mechanisms.

Adult↗