SAA-only HDL formed during the acute phase response in apoA-I+/+ and apoA-I-/- mice.

Serum amyloid A (SAA) is an acute phase protein of unknown function that is involved in systemic amyloidosis and may also be involved in atherogenesis. The precise role of SAA in these processes has not been established. SAA circulates in plasma bound to high density lipoprotein-3 (HDL3). The pathway for the production of SAA-containing HDL is not known. To test whether apolipoprotein (apo)A-I-HDL is required in the production of SAA-HDL, we analyzed the lipopolysaccharide (LPS)-induced changes in apoA-I+/+ and apoA-I-/- mice. In apoA-I+/+ mice, after injection of LPS, remodeling of HDL occurred: total cholesterol increased and apoA-I decreased slightly and shifted to lighter density. Dense (density of HDL3) but large (size of HDL2 ) SAA-containing particles were formed. Upon fast phase liquid chromatography fractionation of plasma, >90% of SAA eluted with HDL that was enriched in cholesterol and phospholipid and shifted "leftward" to larger particles. Non-denaturing immunoprecipitation with anti-mouse apoA-I precipitated all of the apoA-I but not all of the SAA, confirming the presence of SAA-HDL devoid of apoA-I. In the apoA-I-/- mice, which normally have very low plasma lipid levels, LPS injection resulted in significantly increased total and HDL cholesterol. Greater than 90% of the SAA was lipid associated and was found on dense but large, spherical HDL particles essentially devoid of other apolipoproteins.We conclude that serum amyloid A (SAA) is able to sequester lipid, forming dense but large HDL particles with or without apoA-I or other apolipoproteins. The capacity to isolate lipoprotein particles containing SAA as the predominant or only apolipoprotein provides an important system to further explore the biological function of SAA.

Nascent astrocyte particles differ from lipoproteins in CSF.

Little is known about lipid transport and metabolism in the brain. As a further step toward understanding the origin and function of CNS lipoproteins, we have characterized by size and density fractionation lipoprotein particles from human CSF and primary cultures of rat astrocytes. The fractions were analyzed for esterified and free cholesterol, triglyceride, phospholipid, albumin, and apolipoproteins (apo) E, AI, AII, and J. As determined by lipid and apolipoprotein profiles, gel electrophoresis, and electron microscopy, nascent astrocyte particles contain little core lipid, are primarily discoidal in shape, and contain apoE and apoJ. In contrast, CSF lipoproteins are the size and density of plasma high-density lipoprotein, contain the core lipid, esterified cholesterol, and are spherical. CSF lipoproteins were heterogeneous in apolipoprotein content with apoE, the most abundant apolipoprotein, localized to the largest particles, apoAI and apoAII localized to progressively smaller particles, and apoJ distributed relatively evenly across particle size. There was substantial loss of protein from both CSF and astrocyte particles after density centrifugation compared with gel-filtration chromatography. The differences between lipoproteins secreted by astrocytes and present in CSF suggest that in addition to delivery of their constituents to cells, lipoprotein particles secreted within the brain by astrocytes may have the potential to participate in cholesterol clearance, developing a core of esterified cholesterol before reaching the CSF. Study of the functional properties of both astrocyte-secreted and CSF lipoproteins isolated by techniques that preserve native particle structure may also provide insight into the function of apoE in the pathophysiology of specific neurological diseases such as Alzheimer's disease.

Production of small high-density lipoprotein particles after stimulation of in vivo lipolysis in hypertriglyceridemic individuals: studies before and after triglyceride-lowering therapy.

In hypertriglyceridemic states, triglyceride enrichment of high-density lipoprotein (HDL) may play an important role in decreasing the HDL cholesterol and apolipoprotein (apo) A-1 plasma concentration. We have shown previously that HDL particles are transformed into small HDLs when lipolysis is stimulated in vivo or in vitro, and this process is more marked if the HDL is triglyceride-rich. The present study was conducted to determine whether the susceptibility of HDL to transformation can be altered by triglyceride-lowering therapy in humans. Seventeen moderately hypertriglyceridemic individuals (nine with type II diabetes mellitus and eight moderately hypertriglyceridemic nondiabetic subjects) were studied before and after 3 months of triglyceride-lowering therapy with gemfibrozil. Since no significant differences in postprandial and postheparin HDL metabolism were detected between type II diabetic and nondiabetic subjects, results are reported for the two groups combined (N = 17). Fasting HDL was triglyceride-rich with a preponderance of HDL3, and became more enriched with triglycerides postprandially. Heparin administration resulted in a rapid decrease in plasma and HDL triglycerides and an increase in plasma and HDL free fatty acids (FFAs). Postheparin, there was a reduction in HDL size and an increase in the proportion of small (HDL3c) HDL particles (HDL3c constituted 7.1% +/- 1.8% of total HDL preheparin and 26.6% +/- 3.8% postheparin, P < .001). Triglyceride-lowering treatment resulted in a decrease in fasting triglycerides (-54%, P < .001) and HDL triglyceride content (-36%, P = .002), an increase in fasting HDL cholesterol (19%, P = .004), and proportionately fewer (13.2% +/- 2.1%, P < .001) HDL3c particles formed postheparin. Postheparin HDL size correlated inversely with the fasting triglyceride level (r = -.55, P < .001) and HDL triglyceride concentration (r = -.34, P = .02). These results show that the postprandial increase in triglyceride levels in hypertriglyceridemic subjects is associated with increased production of small HDL particles when lipolysis is stimulated, and that lipid-lowering therapy can contribute to favorably reduce this postprandial production of small HDL particles. Further studies are needed to clarify how these abnormalities ultimately lead to a decrease of plasma HDL cholesterol and apo A-1 in hypertriglyceridemic states.

Serum amyloid A and high density lipoprotein participate in the acute phase response of Kawasaki disease.

In this study we report changes in HDL concentration and composition in acute and convalescent Kawasaki disease. Notable reductions in plasma HDL-cholesterol (0.54 +/- 0.2 mmol/L, normal level 0.7-1.81 mmol/L) and apolipoprotein A-I (apoA-I) (56 +/- 28 mg/dL, normal level 141 +/- 22 mg/dL) were observed in all 24 patients studied during the acute phase of Kawasaki disease. These changes were accompanied by the marked appearance of serum amyloid A (SAA) protein in the plasma, associated with HDL3-like lipoprotein particles. The distribution of apoA-I was analyzed in five patients and showed a significant increase in lipid-free apoA-I in the bottom fraction (28.8 +/- 4.1%, normal range 10-15%), suggesting displacement of apoA-I from the HDL particles by SAA. Within 2 wk after acute Kawasaki disease, levels of HDL-cholesterol and apoA-I returned to the normal range, and SAA disappeared from the plasma. The HDL of patients with Kawasaki disease was markedly enriched in triglyceride even in the absence of changes in total plasma triglyceride. The core composition of HDL returned to the normal range more slowly than the plasma HDL-cholesterol and apoA-I levels. This suggests that Kawasaki disease has a profound effect on the lipoprotein profile acutely and a more subtle sustained effect on the HDL composition. We interpret these changes as manifestations of the acute phase response in Kawasaki disease.

HDL content and composition in acute phase response in three species: triglyceride enrichment of HDL a factor in its decrease.

High density lipoprotein (HDL) levels decrease during the acute phase response (APR). We have used the APR model of rabbit, baboon, and mouse to study the factors that influence HDL level. In the baboons and rabbits there was massive hypertriglyceridemia, triglyceride enrichment of HDL (60-80% of core lipids), decreases of HDL-cholesterol and apolipoprotein (apo)A-I (to 10% of baseline), and increases of apoA-I in the non-lipoprotein bottom fraction suggesting dissociation of apoA-I from the particles. Detailed analyses of serum amyloid A (SAA)-rich HDL done in the rabbit revealed large, triglyceride-enriched (> 60% of core lipids) particles containing > 95% SAA. These particles had a high surface to core ratio (13.4 +/- 1.94, control = 3.0 +/- 0.12) and a very high protein (79.71 +/- 5.25 weight %, control = 37.2 +/- 0.43) proportion, large (r = 5.95 nm) when examined by non-denaturing gradient electrophoresis but small when examined by electron microscopy (r = 4.2 nm). In the mouse there was no hypertriglyceridemia, no triglyceride enrichment of HDL, no decrease of HDL cholesterol. ApoA-I decreased to about 61.4% of baseline but did not increase in the bottom fraction although large but dense SAA-enriched HDL particles were also produced. These results suggest that hypertriglyceridemia, triglyceride-enrichment of HDL, and dissociation of apoA-I from the particles, possibly by displacement of apoA-I by SAA, are important factors in the decline of HDL during the APR. Whether differences in triglyceride metabolism account for the differences in the HDL response in the species studied requires further experimentation.

Postprandial changes in high-density lipoprotein composition and subfraction distribution are not altered in patients with insulin-dependent diabetes mellitus.

A detailed analysis of postprandial changes in the size, density, composition, and relative proportion of the major high-density lipoprotein (HDL) subfractions, HDL2 and HDL3, was performed in seven normolipidemic patients with insulin-dependent diabetes mellitus (IDDM) in moderate glycemic control and seven age-, sex-, and weight-matched healthy nondiabetic controls. IDDM subjects received an overnight insulin infusion to maintain euglycemia, with an incremental increase in the insulin infusion rate at the time of the test meal (containing 60 g fat/m2). Samples for detailed analysis of HDL by gradient density ultracentrifugation and nondenaturing gradient gel electrophoresis (GGE) were collected at 0, 4, Br, and 12 hours after the test meal. The composition of HDL, HDL2, and HDL3 was significantly altered in the postprandial state in IDDM subjects and controls with an increase in triglyceride content at 4 to 8 hours and a reciprocal decrease in cholesteryl ester, reflecting exchange of lipid constituents of HDL with triglyceride (TG)-rich lipoproteins. In addition, the phospholipid content of the particles increased at 8 hours after the meal. Peak density of HDL2 and HDL3 decreased slightly at 4 to 8 hours, reaching significance only in controls at 8 hours (P < .05), whereas the mean radius size of these subfractions did not change significantly. In controls and IDDM subjects, the ratio of HDL3 to HDL2 at 8 to 12 hours increased significantly (P < .005). Significant differences in the composition, size, density, or subfraction distribution of HDL between subjects with IDDM and controls were not observed following ingestion of the lipid-rich meal. We conclude from these data that in patients with IDDM in moderate glycemic control, there do not appear to be any significant gross abnormalities in postprandial HDL metabolism with respect to the size, density, or compositional changes of HDL particles.

Heparin-induced lipolysis in hypertriglyceridemic subjects results in the formation of atypical HDL particles.

This study reports on the characterization of high density lipoprotein (HDL) in normotriglyceridemic and hypertriglyceridemic (HTG) subjects, after a fat meal and heparin-induced release of lipases. Samples for detailed analysis of HDL by density gradient ultracentrifugation and nondenaturing gradient gel electrophoresis were collected at 0 h and 5 h after the meal and 15 min after the administration of heparin. The normotriglyceridemic subjects were subdivided into two groups: those who remained normotriglyceridemic 5 h after the meal (NTG) or those who were hypertriglyceridemic at this time point (NTG-HTG). At the outset of the study, mean triglyceride levels were significantly higher (P < 0.001) and HDL cholesterol levels lower (P < 0.02) in the HTG group. The HDL particles in this group were enriched with triglyceride (P < 0.001). Serum triglyceride levels rose in all three groups after the fat meal and this was associated with further triglyceride enrichment of the HDL particles. In all groups, rapid lipolysis induced by heparin caused a significant decrease in plasma triglycerides and increase in free fatty acid levels, these changes being greatest in the HTG group. HDL density profiles of the study groups prior to the administration of heparin demonstrated two distinct peaks at density 1.09 g/ml (HDL2) and 1.13 g/ml (HDL3). However, after the administration of heparin to the HTG group, only a single peak in the HDL profile was evident that was located at the density region corresponding to HDL2 (1.09 g/ml). Upon gradient gel electrophoresis of this peak, there was an increased number (P < 0.005 vs. NTG) of small particles (< 4.37 nm) whose size was similar to the size range normally associated with HDL3b and HDL3c. Similar changes in HDL density and size after the administration of heparin were observed in the NTG-HTG group who were also hypertriglyceridemic postprandially. By contrast, the density gradient profiles and sizes of the HDL particles did not change after the administration of heparin to NTG subjects. Thus, the activation of lipolysis in HTG subjects leads to the generation of atypical HDL particles that are small but of reduced density. Rapid clearance of such particles could account for the inverse relationship between triglyceride and HDL cholesterol in this population subgroup.

The acute-phase response and associated lipoprotein abnormalities accompanying lymphoma.

Lipoprotein abnormalities seen in patients with inflammatory diseases are thought to develop secondary to circulating cytokines and the accompanying acute-phase response. Patient's with lymphoma may develop similar lipoprotein abnormalities but the mechanism is unclear. We report a patient with B-cell lymphoma who presented with an HDL cholesterol level of 3 mg dl-1, an ApoA level of 17.4 mg dl-1, elevated triglyceride level (272 mg dl-1) and an elevated ApoB level of 156 mg dl-1. Density gradient analysis of the patient's lipoproteins demonstrated a virtual absence of an identifiable HDL particle. Serum amyloid A and C-reactive protein were also elevated. All of the lipoprotein abnormalities resolved with chemotherapy and resolution of the acute-phase response. The acute-phase response may be associated with striking lipoprotein abnormalities in a subset of patients with lymphoma. Lymphoma should be included in the differential diagnosis of patients with hypertriglyceridaemia and low HDL cholesterol.

Role of basal triglyceride and high density lipoprotein in determination of postprandial lipid and lipoprotein responses.

The present study reports on the interaction between basal triglyceride and high density lipoprotein (HDL) cholesterol in determining the magnitude of postprandial triglyceridemia. The vitamin A fat-loading test was used to label intestinally derived triglyceride-rich particles after a high fat meal in 18 subjects with low HDL cholesterol and 6 control subjects who had normal fasting triglyceride and HDL cholesterol levels. The patients with low HDL cholesterol were divided into 2 groups on the basis of their basal triglyceride concentrations; 11 had normal triglyceride levels, and 7 had elevated serum triglycerides (HTG). In the HTG-low HDL group, the incremental area under the triglyceride curve was significantly greater (P less than 0.0003) than that in the other 2 groups, between whom no significant differences in triglyceride response were observed. Retinyl palmitate levels measured in whole plasma, an Sf greater than 1000 chylomicron fraction, and an Sf less than 1000 nonchylomicron fraction were also significantly greater in low HDL subjects with HTG, while the concentrations in low HDL subjects with normal triglyceride levels and control subjects were similar. Although basal HDL cholesterol levels in all study subjects were negatively correlated with the area under the incremental triglyceride curve (r = -0.42; P less than 0.05), this correlation was weak, in contrast to the correlation between fasting triglyceride levels and incremental triglyceride area (r = 0.56; P less than 0.005). Furthermore, basal HDL cholesterol levels did not correlate with the area under the chylomicron or nonchylomicron curves, whereas basal triglyceride levels were significantly correlated (P = 0.0001) with both of these variables. The HDL particles of both low HDL groups had a significantly higher proportion of triglyceride compared to the HDL particles in the control subjects. In conclusion, 1) fasting triglyceride levels are a more powerful indicator of the postprandial lipid response than basal HDL cholesterol in subjects with low HDL cholesterol levels; 2) patients with low HDL cholesterol levels do not preferentially accumulate chylomicron remnants after a meal unless they have coexisting hypertriglyceridemia; and 3) abnormalities in the levels of triglyceride-rich particles post-prandially are unlikely to be responsible for the increased incidence of atherosclerosis in low HDL patients who are normotriglyceridemic.

Postprandial triglyceride response in type 1 (insulin-dependent) diabetes mellitus is not altered by short-term deterioration in glycaemic control or level of postprandial insulin replacement.

UNLABELLED: The effect of deteriorating glycaemic control on the lipoprotein responses to the ingestion of a high fat meal was investigated in seven normolipidaemic Type 1 (insulin-dependent) diabetic patients and the results were compared with corresponding responses in seven normolipidaemic control subjects. In addition, the importance of insulin in regulating the postprandial lipoprotein responses was examined by comparing the results obtained from the diabetic patients maintained on a basal infusion of insulin throughout the study with those obtained when a step-up, step-down insulin infusion was administered following the meal. Vitamin A was added to the test meal in all subjects to trace the metabolism of the chylomicron (Sf greater than 1000) and non-chylomicron (Sf less than 1000) fractions in the postprandial period. No differences in fasting and postprandial triglyceride levels nor in the concentration of the chylomicron and non-chylomicron fractions were observed between diabetic and control subjects. In the diabetic patients short-term (two-week) deterioration in glycaemic control did not have any adverse influence on the basal and postprandial lipid responses. However, while the amount of insulin administered after the meal in the diabetic patients did not have any effect on the postprandial triglyceride or chylomicron responses, the concentration of non-esterified fatty acids was significantly higher (p less than 0.0005) when only a basal infusion of insulin was administered. IN CONCLUSION: 1) Short-term deterioration in glycaemic control does not adversely affect lipoprotein concentrations in Type 1 diabetes. 2) Non-esterified fatty acids appear to be a more sensitive index of insulinization post-prandially than triglycerides.

Effects of the acute phase response on the concentration and density distribution of plasma lipids and apolipoproteins.

Longitudinal studies were carried out in the rabbit model to determine alterations in the concentration and density distribution of plasma lipids and apolipoproteins during the acute phase response (APR) characterized by elevated levels of C-reactive protein (CRP) and serum amyloid A (SAA). Twelve hr after the intramuscular injection of croton oil, SAA was detectable in high density lipoprotein (HDL). At the height of the response (72 hr), HDL decreased while SAA became the major HDL apoprotein, up to 80% of the proteins in the higher density fractions. The SAA-enriched particles became denser (density of HDL3) but larger (size of HDL2), had slower electrophoretic mobility, and were depleted in apoA-I, cholesterol, triglyceride, and phospholipid. HDL-cholesterol decreased and was redistributed to other fractions while apoA-I disappeared from the circulation. During this time plasma triglycerides increased 6- to 10-fold while plasma cholesterol and phospholipids showed minimal changes. ApoB increased 5- to 6-fold while the apoB-containing particles shifted to higher density resulting in elevated IDL and then LDL during recovery. VLDL (d less than 1.006 g/ml) increased and acquired 30-40% of the plasma triglycerides, cholesterol, phospholipid, and apoB. SAA also increased in VLDL while apoE decreased.

Inflammation-induced changes in rabbit CRP and plasma lipoproteins.

Inflammation is accompanied by changes in the plasma concentrations of "acute phase reactants" including the C-reactive proteins of man and other species. Previous results in our laboratory showed that CRP in rabbit acute phase serum may circulate in association with very low density lipoproteins (VLDL), which influence both the apparent m.w. and electrophoretic mobility of CRP. We now show that the ability of VLDL to interact with CRP varies with time during the acute phase response. Before the induction of inflammation, the factor(s) responsible for the beta-mobility of CRP is present at low levels in the VLDL. During the first 24 hr of the acute phase response, the activity can no longer be demonstrated in the VLDL fraction. By 36 to 48 hr after inflammatory stimulation, a significantly increased level of this factor(s) is measurable in VLDL. Furthermore, during the acute phase response, the alpha-lipoproteins decrease, and the beta- and pre-beta lipoproteins increase. The increase in beta- and pre-beta-lipoproteins is due to an accumulation of VLDL isolated at d less than 1.006 g/ml. These changes are accompanied by marked hypertriglyceridemia and a significant increase in phosphocholine-containing phospholipids. A non-CRP apoprotein present in low amounts in VLDL from normal rabbit plasma appears to increase in VLDL as inflammation progresses. This VLDL apoprotein increases in response to multiple acute phase stimuli and may be a newly recognized acute phase reactant in the rabbit.

Interaction of very low density lipoproteins (VLDL) with rabbit C-reactive protein.

Rabbit CRP is similar to human CRP in structure, kinetics of appearance, and binding reactivities to phosphate esters and cationic polymers. CRP in rabbit acute-phase serum migrates either with gamma or with beta, pre-beta electrophoretic mobility, and distinct gamma- and beta-migrating species can be observed simultaneously in some sera. The present study shows that beta-CRP in serum is converted to gamma mobility during isolation and purification. Normal, acute-phase, or CRP-depleted acute-phase rabbit serum restores the beta mobility of purified gamma-CRP, a conversion that does not occur in the presence of EDTA. Serum CRP fails to adsorb to DEAE-cellulose but does adsorb to CM-cellulose, from which it elutes as gamma-mobility antigen. Chelation by EDTA or flotation and removal of lipoproteins from acute phase rabbit serum produces a gamma-mobility CRP that adsorbs to the anion-exchange resin. Lipid-containing fractions from ion-exchange columns as well as VLDL (but not LDL or HDL) isolated by ultracentrifugation change the mobility of purified CRP from gamma to beta, pre-beta. These changes in mobility are not observed in the presence of EDTA or phosphocholine. In acute-phase rabbit serum with CRP of both beta and gamma mobility, the beta form has a higher m.w. and is lipid-associated, whereas the gamma form is a lower m.w., lipid-poor molecule. These results suggest that in serum the association of CRP with lipoproteins, particularly VLDL, is responsible for its beta, pre-beta electrophoretic mobility. Further studies of the association of CRP with lipoprotein in relation to lipoprotein metabolism may provide insight into the biological role of CRP.

Quantitation of apolipoprotein A-I of human plasma high density lipoprotein.

High density lipoproteins (HDL) may be controlled via their major apolipoprotein, A-I. To study this apolipoprotein, a simple, precise, and accurate immunodiffusion assay for A-I was developed and applied in a sample of Bell Telephone Company employees. A-I showed a slight increase with age in men (r=0.11, n=263) and women (r=0.15, n=257). A-I correlated closely with HDL cholesterol (r=0.72). It was weakly related to total triglyceride in women (r=0.24) but was inversely related in men (r=-0.17). Women on estrogen had the highest A-I levels (149 mg/dl +/- 26, x +/- S.D., n=29, p is less than 0.05), followed by women on combination oral contraceptives (141 +/- 26, n=80) whereas women on no medication had lower levels (129 +/- 25, n=99, p is less than 0.01) but men had the lowest levels (120 +/- 20, p is less than 0.01) In a separate group of 14 women given estrogen for 2 wks (1 mug/kg/day), A-I increased by 24%. Thus A-I is increased by exogenous and, most likely, endogenous estrogen, Among hyperlipidemic referral subjects, those with hypercholesterolemia (n=43) and hypertriglyceridemic women (n=33) had normal A-I levels. Among hypertriglyceridemic men both A-I and HDL cholesterol values were decreased (115 +/- 20, p is less than 0.01 and 37 +/- 3, p is less than 0.01, respectively, n=68) but were significantly lower among a group of myocardial infarction survivors (107 +/- 16, p is less than 0.01, and 27 +/- 6, p is less than 0.01, respectively, n=24). High density lipoprotein levels and the content of cholesterol in HDL associated with A-I appear to be decreased in coronary heart disease.

Purification and characterization of human plasma lecithin:cholesterol acyltransferase.

A highly purified (approximately 12 000-fold) homogeneous preparation of human plasma lecithin:cholesterol acyltransferase (LCAT) with 16% yield was obtained by a combination of density ultracentrifugation, high density lipoprotein affinity column chromatography, hydroxylapatite chromatography, and finally chromatography on anti-apolipoprotein D immunoglobulin-Sepharose columns to remove apolipoprotein D. This enzyme preparation was homogeneous by the following criteria: a single band by polyacrylamide gel electrophoresis in 8 M urea; a single band on sodium dodecyl sulfate gel electrophoresis with an apparent molecular weight of 68 000 +/- 1600; a single protein peak with a molecular weight of 70 000 on a calibrated Sephadex G-100 column. Its amino acid composition was different from human serum albumin and all other apoproteins isolated from lipoprotein fractions.

Immunoassay of human plasma apolipoprotein B.

A specific and precise double antibody immunoassay for human plasma apolipoprotein B (apoB) was developed and applied in normolipidemic and hyperlipidemic subjects. The intra-assay coefficient of variation was ca. 9%. The distributions of total apoB and low density lipoprotein (LDL) apoB in a randomly selected, healthy, fasting population (n = 349) was slightly skewed with a mean total apoB of 81 mg/100 ml and LDL apoB of 72 mg/100 ml. The 90th percentile cutoffs for total apoB and LDL apoB were 106 and 97 mg/100 ml, respectively. Regarding total apoB, women showed a statistically significant increase (r = 0.463, p less than 0.001) with age (30-65) and an average annual increment of plasma apoB of 1.1 mg/100 ml. In contrast, men showed only a slight increase of apoB from the 4th to 5th decade, with an average annual increment of 0.7 mg/100 ml (r = 0.201, 0.02 less than p less than 0.05). Similarly, regarding LDL apoB, women showed an increase of 1.0 mg/100 ml/year from the 4th to 7th decade (r = 0.501, p less than 0.001), whereas men's LDL apoB did not increase significantly with age (r = 0.114, 0.2 less than p less than 0.3, for ages 30-49). Six of ten normal young subjects showed essentially no physiological variation in fasting apoB levels over a 10-wk period, whereas four had a variation of ca. 5% or less. LDL apoB represented ca. 90% of the total apoB in normolipidemic and type II plasma samples (86% in type IV samples) but only 68% in type III plasmas (n = 7). The ratios of LDL cholesterol-LDL apoB were similar for the random and hyperlipoproteinemic groups, ranging from a high of 1.8 for type IIa to a low of 1.5 for type IV. The ratio of cholesterol to apoB was significantly elevated (p less than 0.002) in the d less than 1.006 fraction of the type III plasma samples compared to the random and type II groups.

Lp(a) lipoprotein: relationship to sinking pre-beta lipoprotein hyperlipoproteinemia, and apolipoprotein B.

To assess the relationship between the Lp(a) and the "sinking pre-beta" (d smaller than 1.006) lipoprotein, the concentration of Lp(a) was quantified by radial immunodiffusion and the presence or absence of sinking pre-beta was assessed by agarose electrophoresis in overnight fasting plasma samples from 485 adults, comprised of 320 with normal lipid levels, 48 with type IIa, 40 with type IIb, and 77 with type IV lipoprotein phenotypes. The median Lp(a) level was 7.6 mg/100 ml, 89% (433 of 485) having detectable Lp(a) levels. Twenty-two per cent (107 of 485) had detectable pre-beta lipoprotein in the d greater than 1.006 plasma fraction (sinking pre-beta). Of the sinking pre-beta positive plasma samples, 96% (102 and 107) exceeded the median Lp(a) level, and sinking pre-beta was detected in all 44 samples with an Lp(a) concentration exceeding 40 mg/100 ml. The relationship of Lp(a) and sinking pre-beta to lipoprotein phenotype was assessed. Compared to the normolipidemic group, the type IIa group had higher Lp(a) percentile values (p smaller than 0.02), whereas the IIb and type IV groups had significantly lower Lp(a) values than the normolipidemic group. Ninety-two per cent (296 of 320) of the normolipidemic subjects had detectable levels of Lp(a) and 22% (70 of 320) had detectable sinking pre-beta lipoprotein. Ninety-four per cent (45 of 48) of the type IIa plasmas had detectable Lp(a) levels and 27% (13 of 48) had sinking pre-beta lipoproteins. Contrasted with the IIa group, only 80% (32 of 40) of the IIb plasmas had detectable Lp(a) levels and 18% (7 of 40) had sinking pre-beta lipoprotein. In the type IV plasmas 78% (60 of 77) had detectable Lp(a) and 22% (17 of 77) had sinking pre-beta lipoprotein. Lp(a) or log Lp(a) levels were not correlated with apolipoprotein B levels (n = 485, r = 0.002 or 0.037, respectively). Furthermore, Lp(a) levels remained essentially constant in three subjects whose aprptein B levels were altered in response to pharmacological and/or dietary manipulation. A fourth subject had a 50% increase in Lp(a) but this change did not correlate with apoprotein B changes. Thus, these findings suggest that Lp(a) is metabolically independnet of low density lipoprotein even though it shares the same structural protein, apoprotein B.