High-density Lipoprotein Production Research Articles

The N-terminal Globular Domain and the First Class A Amphipathic Helix of Apolipoprotein A-I Are Important for Lecithin:Cholesterol Acyltransferase Activation and the Maturation of High Density Lipoprotein in Vivo

To investigate the role of the N terminus of apolipoprotein A-I (apoA-I) in the maturation of high density lipoproteins (HDL), two N-terminal mutants with deletions of residues 1-43 and 1-65 (referred to as Delta 1-43 and Delta 1-65 apoA-I) were studied. In vitro, these deletions had little effect on cellular cholesterol efflux from macrophages but LCAT activation was reduced by 50 and 70% for the Delta 1-43 and Delta 1-65 apoA-I mutants, respectively, relative to wild-type (Wt) apoA-I. To further define the role of the N terminus of apoA-I in HDL maturation, we constructed recombinant adenoviruses containing Wt apoA-I and two similar mutants with deletions of residues 7-43 and 7-65 (referred to as Delta 7-43 and Delta 7-65 apoA-I, respectively). Residues 1-6 were not removed in these mutants to allow proper cleavage of the pro-sequence in vivo. Following injection of these adenoviruses into apoA-I-deficient mice, plasma concentrations of both Delta 7-43 and Delta 7-65 apoA-I were reduced 4-fold relative to Wt apoA-I. The N-terminal deletion mutants, in particular Delta 7-65 apoA-I, were associated with greater proportions of pre beta-HDL and accumulated fewer HDL cholesteryl esters relative to Wt apoA-I. Wt and Delta 7-43 apoA-I formed predominantly alpha-migrating and spherical HDL, whereas Delta 7-65 apoA-I formed only pre beta-HDL of discoidal morphology. This demonstrates that deletion of the first class A amphipathic alpha-helix has a profound additive effect in vivo over the deletion of the globular domain alone (amino acids 1-43) indicating its important role in the production of mature alpha-migrating HDL. In summary, the combined in vitro and in vivo studies demonstrate a role for the N terminus of apoA-I in lecithin:cholesterol acyltransferase activation and the requirement of the first class A amphipathic alpha-helix for the maturation of HDL in vivo.

The Polymorphism at Codon 54 of the FABP2 Gene Increases Fat Absorption in Human Intestinal Explants

Based on titration microcalorimetry and Caco-2 cell line transfection studies, it has been suggested that the A54T of the FABP2 gene plays a significant role in the assimilation of dietary fatty acids. However, reports were divergent with regard to the in vivo interaction between this polymorphism and postprandial lipemia. We therefore determined the influence of this intestinal fatty acid-binding protein polymorphism on intestinal fat transport using the human jejunal organ culture model, thus avoiding the interference of various circulating factors capable of metabolizing in vivo postprandial lipids. Analysis of DNA samples from 32 fetal intestines revealed 22 homozygotes for the wild-type Ala-54/Ala-54 genotype (0.83) and 10 heterozygotes for the polymorphic Thr-54/Ala-54 genotype (0.17). The Thr-encoding allele was associated with increased secretion of newly esterified triglycerides, augmented de novo apolipoprotein B synthesis, and elevated chylomicron output. On the other hand, no alterations were found in very low density lipoprotein and high density lipoprotein production, apolipoprotein A-I biogenesis, or microsomal triglyceride transfer protein mass and activity. Similarly, the alanine to threonine substitution at residue 54 did not result in changes in brush border hydrolytic activities (sucrase, glucoamylase, lactase, and alkaline phosphatase) or in glucose uptake or oxidation. Our data clearly document that the A54T polymorphism of FABP2 specifically influences small intestinal lipid absorption without modifying glucose uptake or metabolism. It is proposed that, in the absence of confounding factors such as environmental and genetic variables, the FABP2 polymorphism has an important effect on postprandial lipids in vivo, potentially influencing plasma levels of lipids and atherogenesis.

Induced mutant mouse lines that express lipoprotein lipase in cardiac muscle, but not in skeletal muscle and adipose tissue, have normal plasma triglyceride and high-density lipoprotein-cholesterol levels.

The tissue-specific expression of lipoprotein lipase (LPL) in adipose tissue (AT), skeletal muscle (SM), and cardiac muscle (CM) is rate-limiting for the uptake of triglyceride (TG)-derived free fatty acids and decisive in the regulation of energy balance and lipoprotein metabolism. To investigate the tissue-specific metabolic effects of LPL, three independent transgenic mouse lines were established that expressed a human LPL (hLPL) minigene predominantly in CM. Through cross-breeding with heterozygous LPL knockout mice, animals were generated that produced hLPL mRNA and enzyme activity in CM but lacked the enzyme in SM and AT because of the absence of the endogenous mouse LPL gene (L0-hLPL). LPL activity in CM and postheparin plasma of L0-hLPL mice was reduced by 34% and 60%, respectively, compared with control mice. This reduced LPL expression was sufficient to rescue LPL knockout mice from neonatal death. L0-hLPL animals developed normally with regard to body weight and body-mass composition. Plasma TG levels in L0-hLPL animals were increased up to 10-fold during the suckling period but normalized after weaning and decreased in adult animals. L0-hLPL mice had normal plasma high-density lipoprotein (HDL)-cholesterol levels, indicating that LPL expression in CM alone was sufficient to allow for normal HDL production. The absence of LPL in SM and AT did not cause detectable morphological or histopathological changes in these tissues. However, the lipid composition in AT and SM exhibited a marked decrease in polyunsaturated fatty acids. From this genetic model of LPL deficiency in SM and AT, it can be concluded that CM-specific LPL expression is a major determinant in the regulation of plasma TG and HDL-cholesterol levels.

Familial HDL deficiency characterized by hypercatabolism of mature apoA-I but not proapoA-I.

We have previously described patients with familial high density lipoprotein (HDL) deficiency (FHD) having a marked reduction in the plasma concentration of HDL cholesterol and apolipoprotein (apo) A-I but lacking clinical manifestations of Tangier disease or evidence of other known causes of HDL deficiency. To determine whether FHD in these individuals was associated with impaired HDL production or increased HDL catabolism, we investigated the kinetics of plasma apoA-I and apoA-II in two related FHD patients (plasma apoA-I, 17 and 37 mg/dL) and four control subjects (apoA-I, 126+/-18 mg/dL, mean+/-SD) by using a primed constant infusion of deuterated leucine. Kinetic analysis of plasma apolipoprotein enrichment curves demonstrated that mature plasma apoA-I production rates (PRs) were similar in patients and control subjects (7.9 and 9.1 versus 10.5+/-1.7 mg x kg[-1] x d[-1]). Residence times (RTs) of mature apoA-I were, however, significantly less in FHD patients (0.79 and 1.66 days) compared with controls (5.32+/-1.05 days). Essentially normal levels of plasma proapoA-I (the precursor protein of apoA-I) in FHD patients were associated with normal plasma proapoA-I PRs (7.8 and 10.4 versus 10.9+/-2.6 mg x kg[-1] x d[-1]) and proapoA-I RTs (0.18 and 0.15 versus 0.16+/-0.03 day). The RTs of apoA-II were, however, less in patients (3.17 and 2.92 days) than control subjects (7.24+/-0.71 days), whereas the PRs of apoA-II were similar (1.8 and 1.9 versus 1.7+/-0.2 mg x kg[-1] x d[-1]). Increased plasma catabolism of apoA-II in FHD patients was associated with the presence in plasma of abnormal apoA-II-HDL (without apoA-I). These results demonstrate that FHD in our patients is characterized, like Tangier disease, by hypercatabolism of mature apoA-I and apoA-II, but unlike Tangier disease, by essentially normal plasma catabolism and concentration of proapoA-I.

Role of the carboxy-terminal domain of human apolipoprotein AI in high-density-lipoprotein metabolism--a study based on deletion and substitution variants in transgenic mice.

Cholesterol levels in high-density lipoprotein (HDL) of transgenic mice overexpressing human apolipoprotein AI (apoAI), a des-(190-243)-apoAI deletion mutant or an apoAI-(1-189)-apoAII-(12-77) chimera were 2.8-fold (P<0.001), 1.3-fold (P<0.05) and 2.2-fold (P<0.001) higher than in control mice, respectively. Human apolipoprotein levels in apoAI and in apoAI-(1-189)-apoAII-(12-77) transgenic mice were 5.2-fold and 3.5-fold higher than in des-(190-243)-apoAI transgenic mice, whereas their HDL cholesterol levels were 2.1-fold and 1.6-fold higher. PAGE of HDL isolated by ultracentrifugation revealed that murine HDL migrated as 9.6-nm and 7.2-nm particles. Overexpression of human apoAI and apoAI-(1-189)-apoAII-(12-77) resulted in the production of polydisperse HDL (9.6, 9.2, 8.4 and 7.2 nm) particles, whereas overexpression of des-(190-243)-apoAI primarily resulted in an increase of 7.2-nm particles. The fractional catabolic rates of human apoAI and apoAI-(1-189)-apoAII-(12-77) were very similar, whereas that of des-(190-243)-apoAI was 4.9-fold higher. The endogenous production rates of human apoAI, des-(190-243)-apoAI and apoAI-(1-189)-apoAII-(12-77) in transgenic mice were very similar. It is concluded that deletion of the carboxy-terminal domain of apoAI reduces its lipoprotein association, resulting in the production of small, phospholipid-rich HDL particles that are cleared more rapidly. Substitution of the carboxy-terminal helices of apoAI with helices of apoAII restores lipoprotein association, resulting in the production of HDL, which migrates as human HDL3 and HDL2. Although the carboxy-terminal domain of the chimera contained more than 80% of the amino acid sequence of apoAII, its HDL-distribution profile in transgenic mice was very similar to that of human apoAI. This study demonstrates the importance of the helical structure of apoAI of the carboxy-terminal domain of apoAI, rather than of its exclusive amino acid sequence, in HDL metabolism.

Production of cholesterol-enriched nascent high density lipoproteins by human monocyte-derived macrophages is a mechanism that contributes to macrophage cholesterol efflux.

Atherosclerotic lesions have a lipid core containing crystals and liposomes enriched in unesterified cholesterol as well as numerous monocyte-macrophages enriched in cholesteryl ester. Sufficient amounts of plasma-derived high density lipoproteins (HDL) may not reach and efficiently remove the cholesterol deposited in lesion macrophages or in the lipid core of lesions. We examined the potential of human monocyte-macrophages to produce nascent HDL and to solubilize cholesterol derived from interaction of monocyte-macrophages with lipoprotein and non-lipoprotein sources of cholesterol. Monocyte-macrophages produced discoidal (25 +/- 6 nm long and 6 +/- 1 nm wide (mean +/- S.D.)) and vesicular (89 +/- 41 nm in diameter) lipoprotein particles following and during enrichment of macrophages with cholesterol from acetylated low density lipoprotein (AcLDL) or cholesterol crystals. During cholesterol enrichment, discoidal particles progressively accumulated in the medium for up to 6 days. In contrast, vesicles did not increase past 2 days of incubation. Both the discoidal and vesicular lipoprotein particles had a peak density of about 1.09-1.10 g/ml. The discoidal particles contained apolipoprotein E (apoE), whereas the vesicles contained a major protein constituent with a molecular mass of 22,000 daltons. The vesicles did not contain detectable apoE and the 22,000-dalton protein was not the 22,000-dalton thrombolytic fragment of apoE. Following cholesterol enrichment of macrophages with AcLDL or cholesterol crystals, macrophages excreted much of their accumulated cholesterol, even in the absence of exogenously added cholesterol acceptors. Most of this excreted cholesterol was recovered from the culture medium and was carried in the apoE discoidal particles that showed cholesterol enrichment up to a 2:1 unesterified cholesterol to phospholipid molar ratio. The findings suggest that sufficient production of these nascent HDL by macrophages within atherosclerotic lesions should facilitate removal of cellular and extracellular cholesterol, even in the absence of plasma-derived HDL.

Lipoprotein Metabolism in Normolipidemic Obese Women during Very Low Calorie Diet

We examined changes in high density lipoprotein (HDL) metabolism during a very low calorie diet weight reduction program in 6 massively obese normolipidemic women. The diet protocol consisted of a 1st low calorie diet (LCD; 1440, 1280, and 880 kcal daily for 1 week, each, in succession), a 1st very low calorie diet (VLCD; 420 kcal daily for 4 weeks, using Optifast 70), intermission (880 kcal daily for 1 week), the 2nd VLCD (4 weeks) and the 2nd LCD (880 and 1280-1440 kcal daily for 1 week, each). Mean body weight reduction was 18.9 kg. HDL-cholesterol, more specifically HDL2-cholesterol, reduced transiently during the 1st VLCD, intermission, and 2nd VLCD periods, and tended to increase in the 2nd LCD. Apolipoprotein (apo) A-I showed a similar change to HDL-cholesterol. However, apo A-II decreased persistently throughout the weight reduction program, and the apo A-I/apo A-II ratio increased significantly in the later part of the program. Serum triglyceride, apo B, and lipoprotein lipase (LPL) activity in post-heparin plasma did not change. These data suggest that the observed decrease in HDL-cholesterol was not due to a reduction in very low density lipoprotein-derived HDL production or to an LPL deficiency, but was consistent with reduction in chylomicron-derived HDL formation following dietary fat restriction.

Dietary Palmitic Acid (16:0) Enhances High Density Lipoprotein Cholesterol and Low Density Lipoprotein Receptor mRNA Abundance in Hamsters

In order to examine the qualitative effect of different fats and specific fatty acids on plasma lipids and lipoprotein metabolism, six low fat, cholesterol-free diets were fed to young male hamsters (10/group) for a 4-week period. Fat blends were formulated with coconut oil, palm oil, soybean oil, high oleic acid safflower oil, butter, corn oil, and canola oil. Diets contained 13% energy as fat and dietary polyunsaturate/saturate ratios ranged from 0.12 to 1.04, one of which incorporated the American Heart Association-recommended concentrations of saturates, monoenes, and polyenes and another reflected the current American Fat Blend. In three diets the polyunsaturate/monounsaturate/saturate ratio was held constant while only the 12:0, 14:0, and 16:0 were varied. Plasma lipoproteins and apoproteins were assessed in conjunction with the abundance of specific hepatic and intestinal mRNA for the low density lipoproteins (LDL) receptor and various apolipoproteins associated with cholesterol metabolism. The plasma cholesterol response was lowest with the American Heart Association blend and equally elevated by the more saturated, low polyene diets (polyunsaturate/saturate, 0.12-0.38). Replacing 12:0 plus 14:0 from coconut oil with 16:0 as palm oil induced a significant increase in high density lipoprotein (HDL) cholesterol with a trend toward decreased LDL. These shifts in lipoprotein cholesterol were corroborated by measures of the LDL/HDL ratio, the plasma apolipoprotein B/apolipoprotein A1 ratio, and differences in the synthesis of apolipoproteins and the LDL receptor based on estimates of the mRNA for these proteins in the liver and gut, using specific cDNA probes for apolipoprotein A1, apolipoprotein B, apolipoprotein E, and the LDL receptor. Although it has been suggested that dietary polyenes lower total plasma cholesterol, including HDL, and that saturated fat increases both these pools of cholesterol, the current data represents the first evidence that a specific saturated fatty acid, i.e., palmitic acid, may enhance HDL production.

EFFECTS OF EXERCISE AND FAT INGESTION ON HIGH DENSITY LIPOPROTEIN PRODUCTION BY PERIPHERAL TISSUES

The peripheral production of high density lipoprotein (HDL) cholesterol and of the subclasses HDL2 and HDL3 was assessed by measurement of the arteriovenous fluxes across the human forearm, at rest and after 20 min isometric exercise in the forearm. Eight subjects were studied twice—fasting and after a high-fat meal—and one other subject was studied only after fat loading. In the fasted state the net fluxes of HDL2 and HDL3 cholesterol were slightly negative in the resting forearm, but they became positive during exercise, indicating greater production during short-term muscular activity. The effect of exercise, particularly that on HDL3 cholesterol, was greatly increased by a high-fat meal; the difference in HDL3 cholesterol arteriovenous flux between rest and exercise was significant (-0·06 [SEM 0·05] vs 0·51 [0·17] μmol/100 ml forearm/min). By contrast, there was no peripheral production of HDL2 or HDL3 cholesterol during exercise in two patients with lipoprotein lipase deficiency. These findings suggest that formation of HDL3 during lipolysis by lipoprotein lipase in the muscle capillary bed is influenced by the supply of chylomicrons and other lipoprotein substrates for this enzyme. Muscle blood flow may therefore be an important determinant of HDL production by this mechanism. The effect of exercise in raising HDL cholesterol, and the inverse relation between exercise and coronary heart disease, may be partly the result of this process.

High density lipoprotein metabolism in a rabbit model of hyperalphalipoproteinemia

The potential utility of an animal model of hyperalphalipoproteinemia for examining the role of high density lipoprotein (HDL) in atherogenesis prompted the current studies. Preliminary data indicated that in rabbits high-coconut oil feeding for 30 days doubled plasma HDL-cholesterol levels, but did not affect lower density lipoproteins (LDL) ( d < 1.063 g/ml). Experiments were performed to examine the composition of these HDL and to determine the mechanism for the diet-induced increase in plasma HDL. Rabbits were fed commercial chow or chow plus 14% (w/w) coconut oil and blood samples were collected 18 h after feeding. Compared to chow-fed rabbits, peak levels of HDL-cholesterol were attained within 2 weeks, and coconut oil feeding doubled the plasma levels of HDL-cholesterol, phospholipids and protein for up to 4 months without affecting HDL lipid and apoprotein composition. After 3 months the diet also increased VLDL- (107%) and LDL-cholesterol (40%) levels, but the absolute increases in each of these lipoprotein fractions was less than half of that of HDL. Isotope kinetic studies of 125I-HDL protein indicated a doubled rate of production of HDL and no change in the efficiency of removal of HDL from plasma. These studies demonstrate that in the rabbit high-coconut oil feeding doubles the rate of production and turnover of apparently normal HDL particles. It is proposed that such an animal model could be utilized to examine directly the role of HDL in atherogenesis.

Lipoprotein Metabolism in a Rat Model of Diet-Induced Adiposity

Obesity in Humans is associated with decreased plasma levels of high density lipoprotein (HDL), but the mechanisms effecting this relationship have not been established. Four treatment groups were used to develop a range of moderate adiposity: rat pups were raised in litters of 4 or 14 and fed from weaning diets of 6 or 24% fat (wt/wt) for 15–17 wk. Lipoproteins from plasma and from a recirculating in situ liver perfusion system were then separated and analyzed, lipoprotein lipase (LPL) activity was assayed in samples of adipose tissue and skeletal muscle and body composition and cholesterol concentrations of various tissues were determined. There was little effect of the diet or litter size treatments on plasma lipids or lipoprotein profiles. Compared to the marked changes in lipid and lipoprotein metabolism that have been observed in severely obese animal models, there was generally little effect of the treatments used to produce this model of moderate diet-induced adiposity. Adiposity was unrelated to plasma total cholesterol and triglycerides. While fatness was positively, although weakly, correlated with plasma levels of several HDL components, including HDL cholesterol, there were no consistent treatment effects on these measures. Plasma HDL levels and adiposity were unrelated to hepatic HDL production or tissue LPL activities. A review of the literature suggests that differences in plasma HDL responses to adiposity in humans and in experimental animals may be due to inherent species differences in lipoprotein metabolism.

Significance of hepatic triglyceride lipase activity in the regulation of serum high density lipoproteins in type II diabetes mellitus.

We investigated the regulation of serum high density lipoprotein (HDL) cholesterol metabolism in patients with type II diabetes mellitus by determining the activities of the two lipolytic enzymes that play major roles in the production and degradation of HDL. The activity of lipoprotein lipase (LPL), the enzyme responsible for HDL cholesterol production, and the activity of hepatic triglyceride lipase (HTGL), the enzyme that facilitates the catabolism of HDL, were measured in plasma obtained after iv injection of heparin. Thirty patients were selected to represent a wide range of serum HDL cholesterol concentrations (low, normal, and high HDL cholesterol groups). Mean lipoprotein lipase activity was similar in all three groups [122 +/- 10 (SEM) U/mL in the low HDL, 141 +/- 11 U/mL in the normal HDL, and 148 +/- 30 U/mL in the high HDL group]. Mean HTGL activity was markedly decreased in the high HDL group; the mean values were 346 +/- 28 U/mL in the low HDL, 320 +/- 25 U/mL in the normal HDL, and 191 +/- 23 U/mL in the high HDL groups, respectively. Body weight and insulin requirement correlated directly with HTGL activity and inversely with serum HDL cholesterol levels. These findings suggest that in type II diabetes mellitus low serum HDL cholesterol levels may be due to an increased rate of clearance by HTGL.

The effects of marked caloric restriction on lipoprotein lipase-activators in obese subjects

Lipoprotein lipase plays a major role in the clearance of triglyceride rich lipoproteins, chylomicrons and very low density lipoproteins, from the circulation and also contributes to production of high density lipoproteins. To be functional lipoprotein lipase requires an activator which is present in the serum. Generally, serum triglyceride correlates positively with serum lipoprotein lipase-activator levels. During caloric restriction both serum triglyceride and adipose tissue liproprotein activity decrease. Affect of caloric restriction on serum lipoprotein lipase activator levels in not known. In this study we have evaluated the effect of marked caloric restriction on the levels of serum triglyceride, total cholesterol high-density lipoprotein cholesterol and lipoprotein lipase-activator in morbidly obese subjects. Initially, twenty subjects were included in the study. Twenty subjects consumed a 320kcal protein supplemented modified fast diet for three weeks, fourteen subjects for seven weeks and eight subjects for eleven weeks. Weight loss was continuous throughout the study. Serum triglycerides decreased during the first three weeks (Baseline 156±9 mg/dl, third week 119±9 mg/dl, p<0.01), followed by a plateau between third and fifth weeks and a small increase, from the fifth through the eleventh weeks. At eleven weeks serum triglycerides were not significantly lower than at the onset of caloric restriction. Serum total-cholesterol changed similarly showing a rapid and significant decline during the first five weeks, a plateau between fifth and seventh weeks and a small increase between ninth to eleventh weeks. However, at eleven weeks, serum cholesterol was significantly lower (Baseline 216±13 mg/dl, eleventh week 140±5 mg/dl, p<0.01). Serum high-density lipoprotein cholesterol level decreased significantly only in female subjects (Baseline 53±2 mg/dl, third week 37±2 mg/dl, p<0.01). Serum lipoprotein lipase-activator level increased steadily reaching approximately 200% of initial levels at week eleven (p<0.01). Thus, it appears that severe caloric restriction in morbidly obese subjects was associated with a significant decrease in the serum total cholesterol, a significant decrease in HDL-cholesterol in women. These decreases seen in serum lipids were limited to the first five weeks despite a continuous weight loss throughout this study. Serum lipoprotein lipase-activator level increased steadily and changes in serum lipoprotein lipase activator levels did not follow the changes in serum triglyceride levels during the caloric restriction.

Serum and urinary high density lipoproteins in glomerular disease with proteinuria

The serum lipoprotein concentrations, including high-density lipoprotein (HDL) subfractions and apolipoproteins Al and B were measured in 21 patients (14 male and seven female) with nephrotic range proteinuria (greater than 3g/24hr), well maintained renal function (creatinine clearance greater than 35 mliter/min/1.73m2) and biopsy-proven primary glomerular disease. In these, and in a further five patients (creatinine clearance greater than 15 mliter/min/1.73m2), urinary apolipoprotein Al output was determined. Total HDL cholesterol was similar in patients and controls, but in male patients, HDL2 was low (0.54 +/- 0.10 mmole/liter, mean +/- SEM) compared to controls (0.75 +/- 0.04 mmole/liter, P less than HDL3 was high (0.81 +/- 0.07 in patients and 0.63 +/- 0.02 mmole/liter in controls, P less than 0.01). In women, there was a similar tendency for HDL2 to be lower in patients (0.68 +/- 0.18 mmole/liter) than in controls (0.85 +/- 0.10 mmole/liter). Multiple regression analysis revealed that major determinants of the urinary apolipoprotein Al output were the urinary protein output and selectivity index (multiple r = 0.85). Furthermore, some patients lost apolipoprotein Al into their urine at rates indicating increased production of apolipoprotein Al in the nephrotic syndrome. The serum HDL subfraction concentrations in the nephrotic syndrome could be explained by a combination of increased HDL production and increased urinary loss of low molecular wt HDL.

Plasma HDL cholesterol and growth hormone in epileptics treated with anticonvulsants.

Plasma high density lipoprotein (HDL) cholesterol and serum growth hormone (GH) levels were determined in 166 epileptic patients undergoing anticonvulsant treatment in 54 healthy controls. HDL cholesterol and GH levels were high in epileptics when compared to the levels in controls. Nineteen out of 31 patients (61%) with elevated GH had elevated plasma HDL cholesterol concentration. This relationship in patients with normal GH was 34/135(25%). In female epileptics with elevated GH plasma HDL cholesterol was in positive relationship to serum GH level (r = 0.47, P less than 0.05). The increase in GH secretion in epileptics might be associated with an increase in hepatic production of HDL.

Effects of estrogen administration on the lipoproteins and apoproteins of the chicken

The plasma lipoproteins of estrogen-treated and untreated sexually immature hens have been compared with respect to their concentration in plasma, protein and lipid composition, particle size, and apoprotein composition. Administration of diethylstilbestrol resulted in a 400-fold rise in the concentration of very low density lipoprotein (VLDL), a 70-fold rise in low density lipoprotein (LDL), and a marked reduction in high density lipoprotein (HDL) protein. It also resulted in the production of LDL and HDL which were enriched in triacylglycerol, while the proportion of cholesterol in all three lipoprotein fractions decreased. In contrast to the lipoproteins from untreated birds, lipoproteins of density less than 1.06 g/ml from estrogen-treated birds were not clearly separable into discrete VLDL and LDL fractions, but appeared to be a single ultracentrifugal class. The apoprotein composition of VLDL and LDL from untreated birds differed from each other; however, the apoprotein patterns of VLDL and LDL from estrogen-treated birds were indistinguishable: both contained a large amount of low molecular weight protein in addition to the high molecular weight component that predominates in the untreated state. The apoprotein composition of HDL was also markedly altered by estrogen administration: the 28 000 mol. wt. protein (apo A-I) decreased in amount from 65% to less than 5% of the total, while a low molecular weight ( M r = 14 000) protein and as yet poorly defined high molecular weight components became predominant. These observations indicate that the hyperlipidemia induced by estrogen administration is accompanied by marked alterations, both qualitative and quantitative, in the plasma lipoproteins.