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Abstract
We studied the individual and occasional changes in lipid metabolism induced by chronic alcohol abuse. In addition, the influence of a detoxication treatment program on the evolutionary changes in some serum lipidic components was studied for a one-year period. Before this program, total cholesterol was above normal, with high values for LP-A cholesterol, whereas for some patients LP-B cholesterol was increased. After the program, there was an increase in total cholesterol, LP-B cholesterol, and apolipoprotein B, with a decrease in LP-A cholesterol. These evolutionary changes continued during the one-year period after the end of the inpatient program.
... That latter point was addressed in the present study by determining the effect of CETP and PLTP on the relative proportions of HDL 2b , HDL 2a , HDL 3a , HDL 3b , and HDL 3c subpopulations both in total human plasma and in reconstituted experimental mixtures containing isolated lipoproteins and purified lipid transfer proteins. More specifically, the cholesteryl ester and phospholipid transfer activities, as well as the size distribution of HDL were investigated in patients with chronic alcoholism, a pathological state that has been shown to be associated with abnormalities in plasma CETP activity (17)(18)(19)(20), HDL profile (21)(22)(23)(24)(25)(26), and as demonstrated for the first time in the present study with alterations in plasma PLTP activity. Thus, alcohol withdrawal provided us with a unique opportunity to study in vivo alterations in plasma lipid transfer activities and to analyze their effects in terms of plasma HDL distribution. ...
... That important issue was addressed in the present study by following simultaneously CETP activity, PLTP activity, and HDL size distribution in total plasma from alcoholic patients before and after alcohol withdrawal. We chose to study the latter parameters in alcoholic patients entering a cessation program for the following reasons: (i) alcohol consumption is known to be associated with marked, significant changes in the level and distribution of plasma HDL (21)(22)(23)(24)(25)(26); (ii) alterations in plasma lipid transfers are suspected to contribute to the alcohol-induced rise in plasma HDL-cholesterol (17)(18)(19)(20); (iii) plasma lipid parameters (18,22,27), distribution of HDL subpopulations (20,38), and plasma lipid transfer activity (17,19,20, and this study) are significantly modified after alcohol withdrawal. ...
... That important issue was addressed in the present study by following simultaneously CETP activity, PLTP activity, and HDL size distribution in total plasma from alcoholic patients before and after alcohol withdrawal. We chose to study the latter parameters in alcoholic patients entering a cessation program for the following reasons: (i) alcohol consumption is known to be associated with marked, significant changes in the level and distribution of plasma HDL (21)(22)(23)(24)(25)(26); (ii) alterations in plasma lipid transfers are suspected to contribute to the alcohol-induced rise in plasma HDL-cholesterol (17)(18)(19)(20); (iii) plasma lipid parameters (18,22,27), distribution of HDL subpopulations (20,38), and plasma lipid transfer activity (17,19,20, and this study) are significantly modified after alcohol withdrawal. ...
The aim of the present study was to investigate the role of the cholesteryl ester transfer protein (CETP) and the phospholipid transfer protein (PLTP) in determining the size distribution of high density lipoproteins (HDL) in human plasma. Whereas both purified CETP and PLTP preparations were able to promote the size redistribution of isolated HDL3, CETP favored the emergence of small HDL, while PLTP induced the formation of both small and large conversion products. When the total plasma lipoprotein fractions isolated from nine distinct subjects were incubated for 24 h at 37 degrees C with either purified PLTP or purified CETP, significant alterations in the relative proportions of the five distinct plasma HDL subpopulations, i.e., HDL2b (9.71-12.90 nm), HDL2a (8.77-9.71 nm), HDL3a (8.17-8.77 nm), HDL3b (7.76-8.17 nm), and HDL3c (7.21-7. 76 nm) were also observed. PLTP induced a significant increase in the relative abundance of HDL2b (8.66 +/- 2.34% versus 7.87 +/- 1. 83% in controls; p < 0.01) and a significant decrease in the relative abundance of HDL3a (32.76 +/- 3.42% versus 37.87 +/- 2.62% in controls; p < 0.05). In contrast, CETP significantly reduced the relative proportion of HDL2a (33.03 +/- 2.53% versus 37.56 +/- 6.43% in controls; p < 0.01) but significantly increased the relative proportion of both HDL3b (21.36 +/- 6.97% versus 15.58 +/- 7.75% in controls; p < 0.01) and HDL3c (3.21 +/- 4.84% versus 1.13 +/- 0.56% in controls; p < 0.05). Finally, in order to assess further the physiological relevance of in vitro observations, CETP activity, PLTP activity, and HDL size distribution were determined in plasmas from 33 alcoholic patients entering a cessation program. Alcohol withdrawal was associated with (i) a significant increase in plasma CETP activity (173.5 +/- 70.5%/h/ml before versus 223.2 +/- 69. 3%/h/ml after alcohol withdrawal, p = 0.0007), (ii) a significant reduction in plasma PLTP activity (473.9 +/- 203.7%/h/ml before versus 312.7 +/- 148.4%/h/ml after alcohol withdrawal, p = 0.0001), and (iii) a significant shift of large HDL2b and HDL2a toward small HDL3b and HDL3c. On the one hand, changes in plasma CETP activity correlated negatively with changes in the proportion of HDL2a (r = -0.597, p = 0.0002) and positively with changes in the proportion of HDL3b (r = 0.457, p = 0.0075). On the other hand, changes in plasma PLTP activity correlated positively with changes in the proportion of HDL2b (r = 0.482, p = 0.0045) and negatively with changes in the proportion of HDL3a (r = -0.418, p = 0.0154). Taken together, data of the present study revealed that plasma PLTP and CETP can exert opposite effects on the size distribution of plasma HDL. PLTP can promote the formation of HDL2b particles at the expense of HDL3a, while CETP can promote the formation of HDL3b particles at the expense of HDL2a.
The chronological development of procedures for determining the cholesterol concentration of in plasma, serum, and whole blood is presented in the review. It is stated that, since the correlation between the risk of development of cardiovascular diseases and the concentrations of total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol in human blood was established by numerous medical studies, procedures for the measurement of these parameters have been developed most actively. A brief overview of these procedures and the results of their comparative testing in patient medical examinations are given. Classifications are proposed for procedures for determining total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol in the blood. The mechanism of action of the chemical reactions taking place in these procedures, advantages and disadvantages, and priorities for their application are considered. Promising directions for the development and improvement of procedures to ensure more accurate measurements of the blood cholesterol concentration, are mentioned, and alternative means of determining the risk of cardiovascular disease are discussed.
Increased levels of serum α-lipoproteins were detected in about 30 per cent of alcoholics submitted for medical care. Abnormal electrophoretic distribution of the α-lipoproteins was common in these cases.
Plasma high density lipoprotein (HDL) concentrations are often increased in chronic alcoholism. The mechanism for this hyperalphalipoproteinaemia was investigated in seven male chronic alcoholics. Determinations of lipoprotein lipase, hepatic lipase and lecithin-cholesterol acyl trailsferase activities and of lipid concentrations in plasma and lipoproteins were made immediately after a debauch and during an abstinence period of 10 days. The lipoprotein patterns registered immediately after cessation of ethanol intake were characterized by elevated concentrations of HDL, especially the HDL2 subclass. Postheparin plasma lipoprotein lipase activities were also increased. During the observation period HDL levels and lipoprotein lipase activities decreased by about 40%. Concomitantly there was a small but significant increase in the concentrations of plasma and very low density lipoprotein (VLDL) triacylglycerol, and of plasma and low density lipoprotein (LDL) cholesterol concentrations. The results suggest that an increased lipoprotein lipase activity and an increased VLDL turnover may contribute to the development of elevated HDL concentration in chronic alcoholism.
Nine young, healthy male volunteers were given ethanol (75 g/day) for 5 weeks. The ethanol was divided into five daily doses and taken so that blood ethanol levels never exceeded 0.04% (w/v).
During the latter part of the ethanol intake period, there was a significant, transient increase of plasma triglyceride (TG) concentrations followed by reduction to normal levels. A three-fold increase of lipoprotein lipase activity (LLA) occurred in biopsy specimens of adipose tissue. An increase of α-lipoprotein concentrations, which correlated significantly with the decrease in plasma TG levels and the increase in adipose LLA, was also observed during the ethanol intake period. No changes were observed in plasma cholesterol and β-lipoprotein levels.
A transient, three-fold increase of TG concentrations occurred in liver biopsy specimens. Ultrastructural and cytochemical examinations of the biopsy specimens showed hyperplasia of the smooth endoplasmic reticulum, and increased canallicular activity of γ-glutamyl transferase (γ-GT) activity in most subjects towards the end of and after the ethanol intake period. Serum γ-GT levels also increased significantly.
Alterations in plasma high density lipoproteins (HDL) were studied in thirty-eight male chronic alcoholics. Twenty-four (63%) of the patients had increased HDL protein (measured immunochemically) and twenty-five (66%) had increased HDL cholesterol (determined after polyanion precipitation of very low density lipoproteins (VLDL) and low density lipoproteins (LDL)). A statistically significant correlation was found between HDL protein and HDL cholesterol (r = 0.39). gamma-Glutamyltransferase (GT) was elevated in eighteen (47%) of the alcoholics. No significant correlations were found between GT and HDL protein or HDL cholesterol. The increase in HDL, as studied by rate zonal ultracentrifugation, was heterogeneous with changes in the HDL2 as well as HDL3 subfractions. It is suggested that determination of HDL total cholesterol, in combination with GT, may represent a valuable and sensitive test for detection of alcoholism.
Data from five study populations participating in the Cooperative Lipoprotein Phenotyping Study indicate strong relations between reported alcohol consumption and blood-lipids. Alcohol consumption was positively associated with high-density-lipoprotein cholesterol level in all populations (r from 0-16 to 0-30), the lipid level appearing to be a graded response even over the low levels of alcohol consumption reported. Less strong but consistently negative correlations were found with low-density-lipoprotein cholesterol. Plasma-triglycerides showed a modest positive correlation with alcohol. The five populations were those of the Albany, Evans County, Framingham, Honolulu, and San Francisco Studies.
Alcohol promotes accumulation of fat in the liver mainly by substitution of ethanol for fatty acids as the major hepatic fuel. The degree of lipid accumulation depends on the supply of dietary fat. Progressive alteration of the mitochondria, which occurs during chronic alcohol consumption, decreases fatty acid oxidation by interfering with citric acid cycle activity. This block is partially compensated for by increased ketone body production, which results in ketonemia. Thus, mitochondrial damage perpetuates fatty acid accumulation even in the absence of ethanol oxidation. Alcohol facilitates esterification of the accumulated fatty acids to triglycerides, phospholipids, and cholesterol esters, all of which accumulate in the liver. The accumulated lipids are disposed of in part as serum lipoprotein, resulting in moderate hyperlipemia. In some individuals with pre-existing alterations of lipid metabolism, small ethanol dose may provoke marked hyperlipemia which responds to alcohol withdrawal. Inhibition of the catabolism of cholesterol to bile salt may contribute to the hepatic accumulation and hypercholesterolemia. The capacity of lipoprotein production and hyperlipemia development increases during chronic alcohol consumption, probably as a result of the concomitant hypertrophy of the endoplasmic reticulum and Golgi apparatus. However, this compensation is relatively inefficient in ridding the liver of fat. This inefficiency may be linked to alterations of hepatic microtubules induced by ethanol or its metabolites, which interfere with the export of protein from liver to serum, promoting hepatic accumulation of proteins as well as fat. As liver injury aggravates, hyperlipemia wanes and liver steatosis is exaggerated. Derangements of serum lipids similar to those found in other types of liver disease also become apparent. The changes in serum lipids may be a sensitive indicator of the progression of liver damage in the alcoholic.
With the realization that alcohol may exert its influence by acting as a direct hepatotoxin, interest has shifted to other areas, especially those concerned with macromolecular metabolism within the hepatocyte. Ethanol and the consequences of its metabolism have a pervasive effect on drug, protein and glycoprotein metabolism. It is these latter actions of ethanol which we particularly hope to emphasize in this review.
Disulfiram, 500 mg/day, raised serum cholesterol levels in alcoholic persons from a mean of 193 +/- 16.4 mg/dl to 227.2 +/- 17.2 mg/dl after 3 weeks and 264 +/- 40 mg/dl after 6 weeks. This increase was not seen in a group taking pyridoxine 50 mg/day in addition to disulfiram 500 mg/day. In contrast to the disulfiram and disulfiram-pyridoxine treatment groups, control groups receiving pyridoxine alone, or no drug, had a 33 mg/dl reduction in serum cholesterol during the first 3 weeks of abstinence, a finding consistent with other evidence showing a rapid decrease in serum lipids on abstinence from alcohol. Patients taking disulfiram 250 mg/day, with or without pyridoxine, did not have this expected decrease in serum cholesterol. Since increased serum cholesterol is one of the risk factors in a coronary heart disease, chronic disulfirm therapy may increase the incidence of arteriosclerotic cardiovascular disease, as has been the case with chronic exposure to carbon disulfide, a principal metabolite of disulfiram.
. The plasma α-lipoprotein levels have been measured in chronic alcoholics admitted to an alcohol clinic. The α-lipoprotein concentration was found to be increased in 60 of 69 patients after recent drinking bouts. The values were as a rule normalized within two weeks. The increase in α-lipoproteins was not correlated with other plasma lipoprotein or lipid alterations, nor was any correlation found between high α-lipoproteins and liver damage detected by analyses of bilirubin, SGOT, SGPT, GT, and bromsulphalein retention tests.
The rate limiting step of fructose metabolism in adipose tissue is fructose transport into the cell. The step is accelerated by insulin only in the absence of glucose, so that insulin has no effect on fructose transport under physiologic conditions. The fructose carrier has a relatively high apparent K m for fructose transport so that significant quantities are transported only at relatively high concentrations of fructose in the blood.
Fructose is the phosphorylated to fructose‐6‐phosphate by the enzyme hexokinase. Glucose does not compete because it is not present intracellularly in sufficiently high concentrations. This statement is correct only for adipose tissue.
Fructose uptake by adipose tissue of diabetic animals is reduced as is glucose uptake, but to a lesser extent.
In vivo, most of the C ¹⁴ ‐incorporation of fructose‐C ¹⁴ into triglycerides or C ¹⁴ O 2 by adipose tissue occurs after hepatic conversion of C ¹⁴ ‐fructose to C ¹⁴ ‐glucose. Insulin is required for glucose transport into adipose tissue.
When an unknown amount of antigen is allowed to diffuse radially from a well in a uniformly thin layer of antibody-containing agar for a sufficient time to allow all antigen to combine, the final area reached by the precipitate is directly proportional to the amount of antigen employed, and inversely proportional to the concentration of antibody. It is also shown that the temperature at which the plates are incubated has no perceptible influence upon the results. By standardizing the technical conditions of the experiment it is possible to use this principle for the immunochemical determination of antigens. In the experimental albumin-antialbumin system here described, the lower limit of the method was found to correspond to 0·0025 μg of antigen, and to an antigen concentrations of 1·25 μg per ml. The standard deviation of the antigen determinations was less than 2 per cent of the mean.
Among non-obese students, those consuming daily 44 g or more of alcohol showed significantly higher incidences of abnormality in glutamic oxalacetic transaminase (GOT) and gamma-glutamyl transpeptidase (gamma-GTP). When daily alcoholic intake of 44 g or more was combined with obesity, highly significant increase in incidences of abnormality in GOT, glutamic pyruvic transaminase (GPT), and gamma-GTP was observed. In normal weight students, even lower range of alcoholic consumption was associated with significant increase in high density lipoprotein (HDL) cholesterol. As compared with normal weight groups, obesity groups showed significantly lower HDL cholesterol, and leanness group significantly higher HDL cholesterol.
The recognition of a possible association between derangements in lipid transport and development of coronary atherosclerosis stimulated a number of epidemiologic studies which indicated a positive correlation between angiographically-proven coronary artery disease and parameters such as elevated plasma lipids, abnormal concentrations and distribution of lipoprotein density classes or electrophoretic bands, and increased levels of VLDL and LDL-cholesterol. Although the relative importance of these parameters has not yet been assessed, it appears that the concentration of LDL with or without elevated levels of VLDL, correlates better with the existence of coronary artery disease than the levels of plasma cholesterol or triglyceride. In a recent study on the quantification of ApoB in aortic intimal homogenates, Hoff and his coworkers have established a statistically significant increase in tightly-bound ApoB with the development of lesions from fatty streaks to fibrous plaques. To assess the potential use of ApoB levels as a risk factor for coronary artery disease, we have quantified plasma ApoB in 232 patients, with angiographically documented coronary, atherosclerosis and in 106 patients with normal coronary arteries. Results of this study show that patients with coronary artery disease had significantly higher levels of all parameters (plasma cholesterol, triglyceride, VLDL-cholesterol, LDL-cholesterol and ApoB) which constitute partially or entirely the ApoB-containing lipoproteins. The concentration of plasma ApoB turned out to be the most significant risk factor in predicting coronary artery disease when the plasma levels of cholesterol were less than 2.65 g/l. These studies underline the significance of apolipoproteins as remarkable markers for monitoring the fate of a variety of lipoprotein particles in normal and deranged lipid transport processes including their role in development of coronary atherosclerosis. The availability of new methodologies for the isolation and quantification of apolipoproteins and lipoprotein families will permit the introduction of these parameters into clinical studies and practice.
High-density lipoproteins (HDL) have been shown to be negatively associated with coronary heart disease; some epidemiologic evidence also suggests that alcohol may protect against coronary heart disease, but other evidence shows the opposite. Alcohol ingestion and even alcoholism may be associated with higher serum HDL levels, but the levels tend to return to normal within 2 weeks with abstinence from alcohol. The relation between HDL and alcoholism, however, is complex, since in addition to alcohol itself several other factors have to be considered. Liver disease and cigarette smoking tend to decrease the serum HDL level in alcoholic persons, while certain hormonal and nutritional influences and the concomitant use of other microsomal-enzyme-inducing drugs may lead to increased HDL levels. On balance, while alcohol per se may increase the serum HDL level, alcoholism--particularly alcoholic liver disease--probably negates the HDL-related protection against coronary heart disease.
The implication of HDL as a negative risk factor in cardiovascular disease has focused on the need for an accurate but rapid routine method for determining HDL-cholesterol in human serum. A practical approach is the specific precipitation of apo-B-containing lipoproteins (atherogenic lipoproteins) by Concanavalin A (Con. A), a lectin with high affinity for glycoprotein apo-B. Specificity was assessed by radial immunodiffusion of apoprotein B in whole serum and in Con. A supernates. Double-immunodiffusion of isolated LP-fractions against anti-apo-B and Con. A demonstrated immunochemical identity of Con. A precipitable LP with apo-B-containing LP. Con. A precipitated cholesterol in the d : 1.063-1.21 g/ml fraction when apo-B was present. Complete precipitation of low density cholesterol was demonstrated, using a reconstituted serum sample radiolabelled in the d less than 1.063 g/ml fraction. Treatment of a reconstituted serum sample containing radiolabelled 125I-apo-A-I with Con. A demonstrated precipitation of trace amounts only of apo A-I. Con. A precipitated LP-B cholesterol quantitatively even when serum triglycerides (TG) exceeded 37.7 mmol/l. Clinical application of this method revealed that 73% of the patient population demonstrated apo-B in the d greater than 1.063 g/ml fraction.
This article has no abstract; the first 100 words appear below.
To the Editor: A lower ouabain binding at one hour in obese subjects, as shown in Figure 1 of the article by De Luise et al. in the October 30 issue, may be a consequence of slower ouabain binding (decreased affinity) rather than of fewer pump sites. It has been shown that ouabain binding is stable and that the dissociation rate is very slow.¹ Thus, values for ouabain binding measured at submaximal concentrations of ouabain at one hour are not steady-state values, since higher values may be obtained with longer incubation. Therefore, it is possible to interpret the data in Figure 1 to indicate . . .
In this study of a normal population from a Midland factory, obesity showed a direct relationship to serum triglyceride and cholesterol levels in males but not in females. High-density lipoprotein (HDL) cholesterol and apolipoprotein A1 levels were not related to obesity in either sex. Alcohol consumption was associated with increased serum triglyceride levels in males but not in females and serum HDL cholesterol levels were also higher in male drinkers only. Cigarette smoking was associated with increased serum triglyceride levels in both sexes but HDL cholesterol levels were reduced only in female smokers. Apolipoprotein A1 levels were not related to smoking in females.
A new procedure for total serum cholesterol and cholesterol esters has been presented. The interference of high concentrations of bilirubin has been eliminated by the inclusion of an adsorbent in the extraction reagents. The procedure for cholesterol esters involves adding an excess of solid digitonin and assaying the cholesterol remaining in solution. We believe it to be the fastest and simplest method yet devised for the determination of cholesterol esters.
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