Raising high density lipoprotein cholesterol. The biochemical pharmacology of reverse cholesterol transport.
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Animals↗
Biomedical subjects
N E Miller
Publications and source records attributed to N E Miller.
Reverse cholesterol transport in the isolated perfused rat spleen.
1. A method has been developed which enables the rat spleen to be loaded in vivo with [3H]cholesterol to a high specific radioactivity using cholesterol-labelled erythrocytes. The erythrocytes were shown to be rapidly degraded by the spleen and not released intact during subsequent perfusion. 2. When labelled spleens were perfused with whole blood or serum, lipoproteins in the high-density lipoprotein (HDL) range were shown to be the principal lipoprotein vehicles for the removal of cholesterol, the specific radioactivity of cholesterol being much greater in the HDL fractions than in other lipoproteins, particularly in the d 1.175-1.210 fraction. 3. The formation of [3H]cholesteryl ester was restricted to the major HDL fractions. 4. Experiments utilizing individual HDL fractions added to a basal perfusate indicated that HDL1 (d 1.050-1.085) was of less importance in the removal of cholesterol from the spleen than HDL subfractions of higher density. Also, a decrease in density of the lipoproteins was observed during perfusion, concurrent with uptake of cholesterol, especially in the d 1.085-1.125 subfraction. 5. When [3H]cholesterol-labelled spleens were perfused with whole blood, about half of the radioactivity released was detected in erythrocytes, indicating a rapid exchange or transport of cholesterol. Thus erythrocytes could play an important role in the transfer of unesterified cholesterol when the chemical potential gradient is favourable.
Animals↗
Don't forget the serratus.
Patients quadriplegic at the C6 level may not be considered candidates for independent transfers and weight shifting because of lack of primary shoulder depressors. However, we have observed that some quadriplegics have been able to use the serratus anterior for this latissimus dorsi function. We present an example of this technique, demonstrated by a patient with a complete C6 injury, and compare him with a subject with normal musculature.
Humans↗
HDL metabolism and its role in lipid transport.
High density lipoprotein (HDL) plays an essential role in plasma lipid transport. It provides a reservoir of C apolipoproteins, which are required for the metabolism of chylomicrons and very low density lipoproteins (VLDL), and acts as a scavenger of surplus unesterified cholesterol from these lipoproteins. HDL is also the major vehicle for the transport of cholesterol from peripheral cells to the liver for excretion and catabolism. This process, known as reverse cholesterol transport, occurs in three stages: extravascular, intravascular, and intrahepatic. In the extravascular phase, unesterified cholesterol is removed from cell membranes by small apoprotein (apo) A-I-containing particles in interstitial fluid. This may be facilitated by binding of the particles to cell surface receptors that recognize apo A-I. After entry into the blood via peripheral lymph, cholesterol in these and other HDL particles is esterified by the associated enzyme, lecithin: cholesterol acyltransferase. Some of the cholesteryl esters that are formed are transferred to chylomicrons and VLDL by a transfer protein. Others are incorporated into the core of HDL particles, which then increase in size and decrease in density. Ultimately these HDL particles associate with apo E, which is synthesized and secreted by some peripheral tissues at a rate regulated by their cell cholesterol content. Removal of cholesteryl esters from the circulation occurs in the liver by receptor-mediated uptake of HDL--with apo E, chylomicron remnants, VLDL remnants, and low density lipoprotein--and by direct transfer of cholesteryl esters from HDL particles into liver cells. Cholesterol is eliminated by hepatocytes by secretion into the bile, and by conversion to primary bile ducts.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Pharmacological intervention for altering lipid metabolism.
Pharmacological intervention for altering plasma levels of lipoproteins is usually aimed at reducing atherogenesis and preventing coronary heart disease (CHD). Drug therapy should be attempted only after other nonpharmacological methods (such as elimination of smoking, weight reduction and exercise) have been tried. An overview of the metabolism of low density lipoprotein (LDL) and high density lipoprotein (HDL) particles is the basis of this paper. Various sites suitable for pharmacological intervention are identified. LDL metabolism can be altered at 2 potential sites, with a consequent reduction in the plasma level of this atherogenic lipoprotein. Hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors (such as lovastatin) and cation-exchange resins (e.g. cholestyramine) reduce LDL levels by stimulating the hepatic synthesis of apolipoprotein (apo) B,E receptors. Very low density lipoprotein (VLDL) secretion is inhibited by nicotinic acid (niacin) and gemfibrozil, leading to a secondary decrease in LDL production from VLDL. Probucol also reduces the LDL concentration and inhibits the oxidative modification of LDL. Gemfibrozil and other fibrates stimulate lipoprotein lipase activity, thereby decreasing VLDL concentration. Reduction of the LDL concentration is effective in reducing CHD incidence, whether this is achieved by stimulation of catabolism or inhibition of production of the lipoprotein. In contrast, the mechanism of raising plasma HDL-cholesterol levels is probably relevant to the potential clinical benefits associated with drug therapy. Gemfibrozil and cholestyramine stimulate synthesis of apoprotein A1, the major protein constituent of HDL particles. Both drugs have been shown to reduce the incidence of CHD in clinical trials, via mechanisms that are related in part to their HDL-raising activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Evaluation of long-term frozen storage of plasma for measurement of high-density lipoprotein and its subfractions by precipitation.
The concentration of high-density lipoprotein cholesterol (HDL-C) in plasma is now established as an independent risk factor for coronary heart disease, but more data are needed on the relative risk-predictive powers of different HDL subclasses. For epidemiologic and clinical purposes, isolation of HDL from other lipoproteins and separation of its two major subclasses, HDL2 and HDL3, are performed most conveniently by precipitation. Although storage of plasma is commonly necessary, little information is available on the long-term stability of HDL subclasses at different temperatures. Therefore, we quantified HDL-C, HDL2-C, and HDL3-C by dual precipitation with heparin-MnCl2/15-kDa dextran sulfate (H-M/DS) in samples of EDTA-plasma from 93 healthy subjects, after storage for one to 433 days at -20 degrees C, at -70 degrees C, or in liquid nitrogen (-196 degrees C). Fourteen samples (15%) were stored for a year or longer. At -20 degrees C, HDL-C decreased by 4.8% per year and HDL3-C decreased by 6.9% per year (P = 0.002 for both variables) relative to results obtained with samples stored in liquid nitrogen; total cholesterol, HDL2-C, and triglyceride did not change significantly at this temperature. When stored at -70 degrees C, none of the lipids showed any change relative to results obtained with liquid nitrogen. Thus, long-term storage of EDTA-plasma at -20 degrees C is unsuitable for subsequent quantification of HDL-C and its subclasses by H-M/DS dual precipitation. Storage at -70 degrees C is preferable, and is as reliable as storage in liquid nitrogen.
Analysis of Variance↗
Cholesterol in ischaemic heart disease.
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Cholesterol↗
Human hepatic low-density lipoprotein receptors: associations of receptor activities in vitro with plasma lipid and apolipoprotein concentrations in vivo.
The relationships of plasma lipid and apolipoprotein (apo) concentrations to hepatic low-density lipoprotein (LDL) receptor activity were examined in 21 subjects (16 females, 5 males), who were undergoing laparotomy for non-neoplastic disease (cholecystectomy in 16). None had familial hypercholesterolemia, or renal, endocrine or hepatic disease. Ages were 37-77 years (mean, 58 years), plasma cholesterol concentrations 4.09-6.72 mmol/l (5.38) and plasma triacylglycerol concentrations 0.75-2.35 mmol/l (1.36). Receptor activity was quantified in vitro as the total saturable binding and EDTA-suppressible binding (representing apoB,E receptors) of 125I-labelled human LDL (15 micrograms protein/ml) by liver homogenate at 37 degrees C. There were no significant differences between men and women in 125I-labeled LDL binding. In the pooled data, EDTA-suppressible binding averaged 50 ng 125I-LDL protein/mg cell protein (S.D., 15). Total saturable binding averaged 2-fold greater (mean, 101 ng/mg; S.D., 32). Plasma cholesterol, LDL cholesterol and apoB concentrations were negative functions of both EDTA-suppressible binding and total saturable binding, but the correlations with EDTA-suppressible binding were stronger (cholesterol: r = -0.59, P less than 0.01; LDL cholesterol: r = -0.48, P less than 0.05; apoB: r = -0.61, P less than 0.01). Plasma triacylglycerol, high-density lipoprotein cholesterol and apoA-I concentrations were not related to either measure of receptor activity. These results provide evidence that the activity of apoB,E receptors in the liver is a major determinant of the plasma LDL concentration in middle-aged and elderly humans.
Adult↗
Plasma lipoproteins and adrenocortical hormones in men--positive association of low density lipoprotein cholesterol with plasma cortisol concentration.
The associations of plasma lipoprotein lipids with the plasma concentrations of two adrenocortical hormones (sampled at 09.00-11.00 h) have been investigated in a random sample of 70 men aged 52-67 yr (mean, 59 yr). Plasma low density lipoprotein (LDL) cholesterol concentration was found to be positively correlated with plasma cortisol, independently of the concentrations of plasma triglyceride, high density lipoprotein cholesterol and androstenedione. After adjusting for covariates, plasma cortisol explained approximately twelve per cent of the variance in LDL cholesterol. These results suggest that plasma cortisol may significantly influence the metabolism of LDL in healthy humans.
Aged↗
Plasma lipoprotein lipids in relation to the MspI polymorphism of the apolipoprotein AII gene in Caucasian men. Lack of association with plasma triglyceride concentration.
Digestion of the human apolipoprotein (apo) A-II gene with the endonuclease MspI produces fragments of 3.0 or 3.7 kb, reflecting the presence or absence of a polymorphic site within an Alu sequence 3' to the gene. Patients with hypertriglyceridemia have been shown to have an increased prevalence of the 3.0 kb allele. To explore this observation further, plasma lipoprotein lipids were studied in a random sample of fasted middle-aged Caucasian men, of which 59 were 3.0 kb homozygotes, 24 were heterozygotes, and 2 were 3.7 kb homozygotes. After adjusting for the effects of age, height, weight, alcohol intake and cigarette consumption by covariance analysis, no statistically significant associations were present between genotype and the concentrations of triglyceride in whole plasma or the d less than 1.019 g/ml fraction of plasma (i.e., VLDL + IDL). Nor were the cholesterol concentrations in VLDL + IDL, low density lipoprotein (LDL, d = 1.019-1.063 g/ml), high density lipoprotein (HDL), HDL2 or HDL3 related to genotype. In an independent comparison of eight 3.0 kb homozygotes and eight 3.7 kb homozygotes (all Caucasians) drawn from a different community, genotype was unrelated to the triglyceride or cholesterol concentrations in VLDL (d less than 1.006 g/ml), IDL + LDL (d = 1.006-1.063 g/ml) or HDL, after adjustment for the effects of covariates. These results suggest that the MspI polymorphism of the apo A-II gene is not associated with genetic variation that significantly affects triglyceride transport in the majority of men.(ABSTRACT TRUNCATED AT 250 WORDS)
Apolipoprotein A-II↗
Self-administration of morphine contingent on heart rate in the rat.
The tendency to associate a given response-reinforcement combination reflects the adaptive significance of the association. Biologically relevant reinforcement can be much more effective in modifying certain responses. For example, treatments that result in various types of illness readily condition aversions to novel flavors, but electric shock is relatively ineffective. While opioid self-administration contingent on lever pressing has been extensively studied, the potential for opioids to reinforce visceral responses remains to be determined. An approach to reinforcing changes in heart rate with drug infusions is described. Methods to control for unconditioned drug effects include reversing the direction of change in heart rate required for infusions and addition of a yoked control subject. In several instances, rats exposed to .1 mg/kg infusions of morphine sulfate contingent on tachycardia showed trends for elevated heart rate, with increased locomotor and grooming activity preceding infusions. Increases in heart rate were most pronounced during daytime, normally inactive periods.
Animals↗
Relationships of plasma lipoprotein concentrations to unbound, albumin-bound and sex hormone-binding globulin-bound fractions of gonadal steroids in men.
Most epidemiologic studies of plasma lipoproteins and gonadal steroids have measured total hormone concentrations only. Gonadal steroids are transported in plasma in unbound, albumin-bound and sex hormone-binding globulin (SHBG)-bound forms, only the first two of which are biologically active. In the present study the associations of plasma lipoproteins with the different fractions of testosterone, oestradiol and 5 alpha-dihydrotestosterone (5 alpha DHT) were explored by multiple regression in 70 men aged 52-67 years (mean, 59 years). The principal finding was that the distribution of cholesterol between the two major subclasses of high density lipoprotein (HDL) was correlated with the concentrations of unbound and albumin-bound oestradiol, but not with SHBG-bound oestradiol or any fraction of testosterone or 5 alpha DHT. These associations were independent of plasma triglyceride. Apoproteins A-I and A-II were not correlated with any hormone fraction. Thus, in middle-aged/elderly men HDL subclasses appear to be influenced by circulating estrogenic activity, but not by androgenic activity, through a mechanism that is unrelated to triglyceride transport or HDL apoprotein metabolism.
Aged↗
Lack of association between plasma lecithin: cholesterol acyltransferase concentration and plasma sex hormone concentrations in men.
Plasma lecithin:cholesterol acyltransferase (LCAT) concentration has been shown to be higher in women than in men, suggesting that sex hormones may influence LCAT metabolism. In order to explore this possibility, the associations of plasma LCAT concentration with the concentrations of total, free and protein-bound testosterone, 5 alpha-dihydrotestosterone and oestradiol in plasma, and with total androstenedione concentration in plasma, were examined in 88 men aged 52-67 yr. Total cortisol in plasma was also assayed. No statistically significant correlations were observed between LCAT and androgen or oestrogen concentrations, but a weak positive association was observed between LCAT and plasma cortisol concentration (r = +0.227, p less than 0.05).
Aged↗
Sex difference in the saturable binding of low-density lipoprotein by liver membranes in ageing rats.
It is well documented that women of child-bearing age tend to have lower serum low-density lipoprotein (LDL) concentrations than men. In order to explore the metabolic basis of this sex difference, we have compared the saturable binding of 125I-labeled LDL (d 1.02-1.05 g/ml) at 37 degrees C by liver membranes from healthy male and female Wistar rats of different ages (15-213 days). Woolf plots of saturable binding curves over the concentration range 15-65 micrograms LDL protein/ml were linear and compatible with a single class of binding sites. Maximum binding capacity (Bmax) was not significantly different in male and female animals of 15-19 days of age (respectively, 0.331 +/- 0.018 vs. 0.427 +/- 0.044 micrograms LDL protein/mg membrane protein, mean +/- S.E.). Thereafter, Bmax increased in females, reaching a peak of 0.635 +/- 0.042 micrograms LDL protein/mg membrane protein at 60 days. As no increase in Bmax occurred in males, values were significantly higher (P less than 0.02) in females than in males (by a mean of 61-117%) at all ages after 30 days. During ageing, serum cholesterol concentration changed reciprocally with Bmax in females (Pearson's correlation coefficient, r = -0.761, P less than 0.01) and remained essentially constant in males. The equilibrium dissociation constant for 125I-labelled LDL binding to the hepatic membranes was unaffected by both age and sex. These results provide evidence that the sex difference in the plasma total and LDL cholesterol concentrations is related, at least in part, to a greater mean LDL receptor density in the livers of females.
Aging↗
Relationship of high density lipoprotein composition to plasma lecithin:cholesterol acyltransferase concentration in men.
The epidemiological associations between the plasma concentrations of several components of high density lipoprotein (HDL) and plasma lecithin:cholesterol acyltransferase (LCAT) concentration have been studied in 101 men aged 52-67 years. Subjects were apparently healthy, and had been selected to provide a wide range of HDL-cholesterol levels. A weak positive correlation was observed between plasma total HDL-cholesterol concentration and LCAT concentration (r = 0.24, P less than 0.02). This reflected an association between HDL3-cholesterol (measured by precipitation) and enzyme concentration (r = 0.21, P less than 0.05). Apoprotein (apo) A-II concentration was also positively correlated with LCAT (r = 0.27, P less than 0.01). HDL2-cholesterol and apo A-I concentration were unrelated to LCAT concentration, as also were the HDL2/HDL3 and HDL-cholesterol/apo A-I ratios. The associations of HDL3 cholesterol and apo A-II with LCAT were strengthened when allowance was made by multiple regression for the effect of log plasma triglyceride; under these circumstances variation in LCAT explained statistically 8% of the variance in HDL3-cholesterol, and 10% of that in apo A-II.
Aged↗
Variations in the apolipoprotein AI-CIII-AIV gene region and in lecithin:cholesterol acyltransferase concentration are determinants of plasma cholesterol concentrations.
We have examined the effects of variation in the region of the apolipoprotein (apo) AI-CII-AIV genes, and in plasma lecithin: cholesterol acyltransferase (LCAT) concentration, on plasma cholesterol concentration in 109 unrelated men aged 52-67 yrs. Restriction fragment length polymorphisms (RFLPs) were detected using the restriction enzymes XmnI, PstI and SstI and individuals were divided into groups using information from all three RFLPs in conjunction. Mean plasma concentrations of both total cholesterol and estimated low density lipoprotein-cholesterol differed significantly (P less than 0.0125) among groups of men with different genotypes. Thus, variation in this gene region may be one of the polygenetic factors involved in determining cholesterol levels in the normal population. In the same subjects, plasma cholesterol was also positively correlated with plasma LCAT concentration (r = 0.55, P less than 0.001), due mainly to an increase in the cholesteryl ester content of apo B-containing lipoproteins with increasing LCAT concentration. Since apolipoproteins AI, CIII and AIV have each been shown to modify the activity of LCAT in vitro, the associations of the RFLPs with plasma cholesterol concentration may reflect changes in LCAT activity secondary to qualitative or quantitative changes in one or more of these apolipoproteins.
Aged↗
Biochemical and pathological features of a modified strain of Watanabe heritable hyperlipidaemic rabbits.
A modified strain of heritable hyperlipidaemic rabbit has been produced by crossing male albino rabbits homozygous for low density lipoprotein receptor deficiency into a coloured commercial colony with strong breeding characteristics. The genetic deficiency has been preserved in the resulting offspring through many generations. Litter numbers, live weight gains and energy intake are similar to normal rabbits. Free and esterified cholesterol in serum, and total cholesterol in very low density plus low density lipoproteins, are markedly increased in homozygote, but only slightly raised in heterozygote, animals. High density lipoprotein-cholesterols show an opposite trend but with less marked differences between the genetic strains. Liver total and esterified cholesterol levels were substantially increased in homozygotes, and the ability of liver membranes to bind human 125I-LDL was markedly reduced, owing to a reduction of the number of high-affinity binding sites. All animals with serum cholesterol values greater than 14 mmol/l at weaning developed extensive aortic atherosclerosis within 16 weeks. The early lesions had the histological appearances of fatty streaks and progressed to complicated disease at 6-12 months. A distinctive pattern of calcific arteriosclerosis, quite different from atherosclerosis, was observed in most aging heterozygote animals and was associated with extensive renal calcium deposition. Corneal arcus developed in some homozygotes but there was no evidence of cerebral atherosclerosis. We conclude that homozygotes of this modified strain can be used for macroscopic studies of the progression of aortic atherosclerosis in the first 4 months after weaning but after this period a combination of macroscopic and microscopic techniques are required. Heterozygotes are unsuitable for studies of this nature.
Animals↗
Plasma cholesterol, ageing and lecithin:cholesterol acyltransferase.
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Adult↗