Showing papers by "Scott M. Grundy published in 1991"
1,900 citations
1,225 citations
TL;DR: β-carotene, like ascorbate and α-tocopherol, inhibits LDL oxidation and might have an important role in the prevention of atherosclerosis.
222 citations
TL;DR: In addition to being as potent as probucol in inhibiting the oxidation of LDL, ascorbate in contrast preserves the endogenous antioxidants in the LDL, which is an important water-soluble, chain-breaking antioxidant in humans.
Abstract: Several lines of evidence indicate that the oxidative modification of low density lipoproteins (LDL) may provide an important link between plasma LDL and the genesis of the atherosclerotic lesion. Ascorbate is an important water-soluble, chain-breaking antioxidant in humans. Probucol, a lipid-soluble antioxidant drug has been shown to retard the progression of atherosclerosis. The aim of the present study was to compare the effects of probucol and physiologic levels of ascorbate on the oxidative modification of LDL in both a cell-free (2.5 microM Cu++ in phosphate-buffered saline) and cellular system (human monocyte macrophages in Ham's F-10 medium). Both ascorbate and probucol inhibited the oxidative modification of LDL in both systems to a similar degree as evidenced by the thiobarbituric acid-reacting substance activity, electrophoretic mobility, and degradation by macrophages. However, whereas co-incubation with physiologic levels of ascorbate resulted in a substantial preservation of the alpha-tocopherol, gamma-tocopherol, and beta-carotene of the LDL, probucol in concentrations ranging from 10 to 80 microM failed to protect these antioxidants. Thus, in addition to being as potent as probucol in inhibiting the oxidation of LDL, ascorbate in contrast preserves the endogenous antioxidants in the LDL.
220 citations
166 citations
TL;DR: The studies presented herein define time-dependent modifications of LDL constituents caused by CuSO4-catalyzed oxidation as well as measurement of oxysterols, which may afford an additional index of the oxidative modification of LDL.
Abstract: The oxidative modification of low density lipoprotein (LDL) may provide a crucial link between plasma LDL and the atherosclerotic lesion. The studies presented herein define time-dependent modifications of LDL constituents caused by CuSO4-catalyzed oxidation. Measurement of the cholesterol content of oxidized LDL by the cholesterol esterase-oxidase assay was found to be inaccurate. The enzymatic assay detected oxysterols as well as cholesterol and thus substantially overestimated the actual cholesterol content. Alteration of electrophoretic mobility and conversion of sterols into oxysterols increased in a parallel, time-dependent manner. Lipid peroxidation, judged by the thiobarbituric acid-reacting substances assay, increased early to maximal values but was not linearly related to either electrophoretic mobility or to oxysterol formation. Neither electrophoretic mobility nor oxysterol formation varied much between repeated oxidative modifications of any given LDL preparation but varied markedly among LDLs from different normolipidemic individuals, suggesting that LDL particles contain some factor conferring susceptibility or resistance to oxidation. Indeed, LDL preparations from different individuals have varying susceptibilities to oxidative modification as evidenced by the three indexes used. The major oxysterol generated was 7-ketocholesterol. Macrophage modification of LDL also resulted in the generation of oxysterols. Thus, measurement of oxysterols may afford an additional index of the oxidative modification of LDL. Since incubation of macrophages with oxidized LDL but not native LDL resulted in the accumulation of oxysterols, this could account for some of the toxic and metabolic effects of oxidized LDL on cells.
139 citations
TL;DR: The effects of beef tallow and cocoa butter, two fats with a high stearic acid content, on serum lipid and lipoprotein concentrations were compared with the effects of butter fat and olive oil in 10 middle-aged men.
127 citations
TL;DR: With the exception of heterozygous FH, most cases of severe hypercholesterolemia appear to be the result of the coexistence of at least two defects in LDL metabolism, and as a rule, they can be treated successfully only by using cholesterol-lowering drugs in combination.
Abstract: This review underlines the concept that multiple factors are responsible for hypercholesterolemia in the American public. Dietary factors (cholesterol, saturated fatty acids, and obesity) clearly raise the cholesterol level, and they are important causes of borderline-high cholesterol. Still, the unexplained decline of LDL receptor activity with aging contributes importantly to borderline-high levels and cannot be ignored. The loss of estrogen-stimulated LDL receptor synthesis after menopause is an important contributor to elevated cholesterol in postmenopausal women. In addition, several genetic defects inherited singly appear to be responsible for moderate hypercholesterolemia. Some of these defects may represent genetic hypersensitivity to diet, and dietary therapy alone may provide adequate cholesterol lowering. Other defects impart resistance to dietary control, and use of a single cholesterol-lowering drug may be required. With the exception of heterozygous FH, most cases of severe hypercholesterolemia appear to be the result of the coexistence of at least two defects in LDL metabolism, and as a rule, they can be treated successfully only by using cholesterol-lowering drugs in combination.
111 citations
TL;DR: Data from the present study reveal that there are several distinct patterns of LDL metabolism responsible for primary hypercholesterolemia, which can serve as the basis for further investigation to determine the molecular defects responsible for each pattern.
Abstract: BACKGROUNDHypercholesterolemia is a well-established risk factor for coronary heart disease. However, the mechanisms underlying hypercholesterolemia, elevated low density lipoprotein (LDL) in particular, are not well understood. To determine these mechanisms, we studied LDL kinetics in a group of men with primary hypercholesterolemia.METHODS AND RESULTSLDL kinetics in 134 middle-aged men with high-risk levels of LDL cholesterol (more than 160 mg/dl) were compared with kinetics in 16 men with borderline high-risk levels of LDL cholesterol (120-159 mg/dl) and 14 men with heterozygous familial hypercholesterolemia (FH). Patients with primary hypercholesterolemia (non-FH) were further divided into moderate hypercholesterolemia (LDL cholesterol, 160-210 mg/dl; n = 108) and severe hypercholesterolemia groups (LDL cholesterol, more than 210 mg/dl; n = 26). Four factors contributed to increasing LDL cholesterol concentrations above the borderline range to moderately elevated levels: 37 patients had no increase in...
71 citations
TL;DR: In patients with primary hypertriglyceridemia, reduction in plasma triglyceride concentrations and increase in LDL-cholesterol concentrations mediated by omega-3 polyunsaturates seem to occur without an increase in LPL or HL activities.
67 citations
TL;DR: The best dietary approach in obese patients with NIDDM, who are relatively early in the course of their disease, is to attempt weight reduction with a lowfat diet.
Abstract: The ideal diet for diabetic patients remains to be determined. Recommendations generally call for low-fat high-carbohydrate diets. The primary purpose of this recommendation is to reduce the risk for coronary heart disease, a major killer of diabetic patients. Some investigators also suggest that high-carbohydrate diets also improve glucose tolerance, even in patients with non-insulin-dependent diabetes mellitus (NIDDM). Another potential advantage of a low-fat diet (high percentage of carbohydrate) is that it may promote weight reduction. High-fat diets are thought by many investigators to stimulate weight gain. Thus, in obese NIDDM patients a trial of a low-fat weight-reduction diet may be worthwhile. However, if after an adequate trial of this diet, weight reduction is not achieved, this suggests that the patient is consuming large quantities of carbohydrates. The continued feeding of a high-carbohydrate diet to a persistently obese patient with NIDDM may have several untoward effects. For example, it can heighten hyperglycemia, raise plasma triglycerides, and lower high-density lipoproteins. In such dietary failures, it may be better to replace carbohydrate with fat to avoid these responses. Ideally, the fat should not raise the serum cholesterol level, and hence it should be unsaturated. Monounsaturated fatty acids seem preferable to polyunsaturated fatty acids, because polyunsaturates may increase the risk for cancer or promote the oxidation of low-density lipoprotein, another potentially atherogenic change. Many NIDDM patients, particularly obese patients in the earlier stages of diabetes, tolerate weight-maintenance high-carbohydrate diets without deterioration of glucose tolerance. However, as their insulin reserve declines, high-carbohydrate diets may further raise glucose levels, and a lower-carbohydrate diet seems preferable. The same may be true for nonobese patients with NIDDM; the predominant defect in many of these patients is a deficient secretion of insulin. Replacement of carbohydrates by monounsaturated fatty acids in the latter two groups of patients may be advantageous. In summary, the best dietary approach in obese patients with NIDDM, who are relatively early in the course of their disease, is to attempt weight reduction with a lowfat diet. However, if this diet should fail, it probably would be better to reduce carbohydrate intake and replace some of it with monounsaturates. Likewise, in more advanced NIDDM, with deficiency of insulin secretion, high-carbohydrate diets probably should be avoided, because they accentuate hyperglycemia. Therefore, the ideal diet for diabetic patients may depend on the presence or absence of obesity, the response to a weight-reduction diet, and the stage of progression of β-cell dysfunction.
TL;DR: Results strongly suggest that an increase in LDL‐receptor activity is the major mechanism whereby LDL levels are lowered during lovastatin therapy.
Abstract: To determine the mechanisms whereby HMG-CoA reductase inhibitors lower the levels of low density lipoproteins (LDL) in patients with mixed hyperlipidaemia, LDL turnover studies were conducted in 12 such patients during placebo and then during treatment with lovastatin. Drug therapy reduced total cholesterol and triglyceride concentrations by 33% and 32%, respectively. During lovastatin therapy, LDL-cholesterol levels fell by 37%, and LDL-apo B concentrations decreased by an average of 29%. The decrease in LDL-apo B concentrations on lovastatin therapy was largely due to an increase in fractional catabolic rates (FCRs) for LDL apo B. The average increase in FCRs was 34%, whereas transport rates (production rates) for LDL apo B remained unchanged. These results strongly suggest that an increase in LDL-receptor activity is the major mechanism whereby LDL levels are lowered during lovastatin therapy. The data do not indicate that this drug inhibited the input of apo B-containing lipoproteins, which would have been expected to result in a decrease in the rate of production of LDL.
TL;DR: By isolation of autologous apoA-I under the conditions described, free apoC-I seemingly provides a valid method for estimating apoS-I turnover, and its use in turnover studies is described.
TL;DR: The data indicate that the degree of postprandial lipemia is not the primary determinant of HDL cholesterol concentrations in endurance-trained men, and the wide range of LDL cholesterol concentrations measured in these men must be attributable to other factors.
Abstract: Previous studies have indicated an inverse relation between circulating high density lipoprotein (HDL) concentrations and the rate of chylomicron clearance. Because chronic exercise has been shown to augment chylomicron clearance, we measured HDL cholesterol concentrations and plasma triglyceride and retinyl palmitate responses to high- (140 g) and low- (50 g) fat meals in endurance-trained men. Plasma HDL cholesterol concentrations in these men ranged from 36 to 105 mg/dl. Intraindividual variation in the cholesterol concentration of the HDLs occurred primarily in HDL2. The magnitude of postprandial lipemia induced by both the high- and the low-fat meals was uniformly low compared with values reported previously for sedentary men and was not correlated with HDL cholesterol concentrations. Postprandial retinyl palmitate concentrations, which reflect chylomicron remnant metabolism, also showed no correlation with HDL cholesterol concentrations. These data indicate that the degree of postprandial lipemia is not the primary determinant of HDL cholesterol concentrations in endurance-trained men. Accordingly, the wide range of HDL cholesterol concentrations measured in these men must be attributable to other factors.
TL;DR: Research carried out to determine the influence of various dietary components, particularly fatty acids and dietary cholesterol, on the risk factors leading to CHD can now be used by industry to provide foods for the future which will provide the public with more healthy choices and hopefully aid in the control of diseases which can be influenced by diet.
Abstract: Dietary habits and the foods we ingest influence health. Nutrition is one factor that can be controlled in such a way as to influence an individual's destiny in such diseases as coronary heart disease (CHD) hypertension, stroke, cancer, osteoporosis, diabetes and gall stone disease. The role of nutrition in treatment and prevention of CHD is one example. It is not only a problem in Western Europe and in the United States anymore but with "westernization" of Asia and Africa and in many Eastern European countries, CHD is increasing at an alarming rate. Led by the American Heart Association, influential groups have provided dietary recommendations to the general public over the past 30 years. These recommendations have been based to a large extent on research carried out to determine the influence of various dietary components, particularly fatty acids and dietary cholesterol, on the risk factors leading to CHD. The results of these investigations can now be used by industry to provide foods for the future which will provide the public with more healthy choices and hopefully aid in the control of diseases which can be influenced by diet.
TL;DR: Kinetic studies of LDL apolipoprotein B were conducted to determine the metabolic differences between the normolipidemic and hypercholesterolemic FH heterozygotes in the family and found normolIPidemic heterozygote had much lower input rates for LDL, together with the higher than usual FCRs for LDL are responsible for the normal concentrations of LDL cholesterol in some of the FH heterogeneity.
Abstract: Heterozygous familial hypercholesterolemia (FH) usually presents with severe elevations of low density lipoprotein (LDL) cholesterol. Recently, a family with FH was described in which several members heterozygous for a mutation in the LDL receptor gene had normal LDL cholesterol levels. Kinetic studies of LDL apolipoprotein B (apo B) were conducted to determine the metabolic differences between the normolipidemic and hypercholesterolemic FH heterozygotes in the family. Studies were performed in 14 family members including the proband (who has homozygous FH), four FH heterozygotes with high LDL levels, four FH subjects with normolipidemia, and five healthy relatives without FH. The proband had a very low fractional catabolic rate (FCR) for LDL (0.15 pool/day). All the FH and non-FH subjects studied, excluding the FH homozygote, had higher than expected FCRs for LDL. The average FCRs for LDL of hypercholesterolemic and normocholesterolemic subjects were not significantly different (0.39 +/- 0.06 versus 0.37 +/- 0.02 pool/day), and these values were 70-80% of those in unaffected relatives. Compared with hypercholesterolemic FH heterozygotes, normolipidemic heterozygotes had much lower input rates for LDL (17.1 +/- author query macros2.6 versus 8.7 +/- 0.9 pools/day, respectively). These low input rates, together with the higher than usual FCRs for LDL, are responsible for the normal concentrations of LDL cholesterol in some of the FH heterozygotes. The low input of LDL could be due to either a decreased secretion of apo B-containing lipoproteins or an enhanced clearance of LDL precursor lipoproteins.
TL;DR: Although it is difficult to separate the effects of diet, leanness, and exercise on the lipid profile, it is apparent that the lifestyle led by these people is associated with a lipid profile that confers an extremely low risk of atherosclerotic disease.
Abstract: Low concentrations of total and LDL cholesterol are associated with minimal risk of atherosclerosis. Aerobic exercise has been similarly associated with a low risk of heart disease. The literature is inconclusive as to whether there is an association between total and LDL cholesterol and exercise. Further, previous work has, almost exclusively, examined male runners. Therefore, we examined 176 male and female cross-country skiers, participating in the National Master's Championships, for body composition, dietary habits, exercise habits, and serum lipid levels. Our results show markedly low concentrations of serum LDL cholesterol and total cholesterol, as well as the expected high concentrations of HDL cholesterol and low concentrations of triglycerides, in these lean skiers. Their diets contained 30% fat, and they exercised 9 h weekly. Although it is difficult to separate the effects of diet, leanness, and exercise on the lipid profile, it is apparent that the lifestyle led by these people is associated with a lipid profile that confers an extremely low risk of atherosclerotic disease.
TL;DR: Consumption of fish, which contain high amounts of n-3 long-chain fatty acids, may have a therapeutic benefit in patients with hypertriglyceridemia and is recommended as a source of fat in their diet.
Abstract: D ietary therapy should always be the first approach to treating hypertriglyceridemia. Dietary factors (caloric content, type of fat, and carbohydrate and alcohol intake) influence serum triglyceride levels through several mechanisms.‘s2 Hypercaloric diets have been shown to stimulate the formation of triglycerides in the liver, promoting the secretion of VLDL particles. In addition, obesity frequently causes secondary hypertriglyceridemia, a condition usually corrected by reducing the caloric intake. Thus, a primary objective of dietary treatment for hypertriglyceridemia is an adequate supply of daily calories in order to achieve and/or maintain the ideal body weight. Regular aerobic physical exercise may be useful both in reducing body weight and in correcting hyperinsulinemia, which is frequently associated with hypertriglyceridemia.3-5 Amounts and types of fats are important in the dietary treatment of hypertriglyceridemia. In familial lipoprotein lipase and apo C-II deficiency (type I), hypertriglyceridemia is aggravated by dietary fat and is best treated by stringent reduction (less than 1520% of daily energy) of fat intake to reduce chylomicron input. An optimal fat intake should be identified for each type I patient, and for most, the diet must be a restricted one.5 Medium chain triglycerides, which are absorbed by the portal vein and do not generate chylomicrons, can be used in cooking or as salad dressing as a supplement to normal dietary long-chain fatty acids once the optimal fat intake has been identified. A transient increase in very-low-density lipoprotein (VLDL) triglyceride may be induced by the high carbohydrate content of very-low-fat diets, but in long-term management, this is of little significance.2 A substantial protein intake (1517% of energy) permits a lower carbohydrate intake.5 Saturated fat intake, in some patients, may increase triglyceride levels, possibly by effecting VLDL metabolism.’ A reduction in the number of hepatic low-density lipoprotein (LDL) receptors has been proposed, and this may also reduce liver uptake of VLDL remnants. Therefore, saturated fatty acids intake should be reduced to less than 10% of daily energy in the dietary management of hypertriglyceridemia. The dietary content of polyunsaturated fatty acids is particularly significant in the hypertriglyceridemic subject. When diets rich in fatty acids of the n-6 series (linoleic acid, c18:2,n-6, present in corn oil) are given to hypertriglyceridemic patients, there is frequently an increase in the fecal excretion of cholesterol and bile acids; a well-known reduction in serum cholesterol also occurs.’ Linoleic acid feeding also lowers triglycerides, although this is not a universal response. In any case, the substitution of linoleic acid for saturated fatty acids is recommended for the dietary treatment of hypertriglyceridemia. Monounsaturated fatty acids will probably serve the same purpose, and they do not have several of the potential disadvantages of high intakes of linoleic acid. Polyunsaturated fatty acids of the n-3 series (fish oils) have been shown to reduce significantly hypertriglyceridemia in hyperlipidemic phenotypes IIb, III, IV and V. Their hypotriglyceridemic action is dose dependent and is explained by a marked reduction of the hepatic synthesis of VLDLtriglycerides.‘j Thus, consumption of fish, which contain high amounts of n-3 long-chain fatty acids, may have a therapeutic benefit in patients with hypertriglyceridemia and is recommended as a source of fat in their diet. In severe hypertriglyceridemias (i.e., type V hyperlipidemia), the use of fish oil capsules has been successfully employed for reducing excess levels of chylomicrons. The optimal dosage, however, remains unknown7 In some diabetic patients with hypertriglyceridemia, the administration of fish oil capsules has impaired diabetic control and increased LDL and
TL;DR: The overall data suggest that the severe hypercholesterolemia in the offspring was due to inheritance of mild to moderate defects of LDL receptor function from both parents, although the latter defects could not be detected with certainty by in vitro tests in each parent.
Abstract: A family is described in which the probands, twin girls, had severe hypercholesterolemia suggestive of familial hypercholesterolemia (FH). The mother of the twins had normal plasma cholesterol levels, and the father had only moderate hypercholesterolemia. Moreover, low density lipoprotein (LDL) binding studies in cultured fibroblasts and isolated lymphocytes in the parents failed to reveal significantly reduced LDL receptor activity that is typical of FH heterozygotes. Turnover studies of LDL in the parents, however, revealed low fractional clearance rates (FCRs) for LDL. In cultured fibroblasts and isolated lymphocytes from the twin probands, binding of normal LDL was half normal or less. LDL turnover studies in the twins revealed a marked reduction in FCRs for LDL. When the twins were treated with lovastatin, however, FCRs for LDL increased significantly, suggesting enhancement of LDL receptor activity. This finding along with LDL binding studies in the cultured cells infer that the twins did not have h...
TL;DR: Barnard suggests that a dietary change such as that employed by the Pritikin Center can markedly improve the lipoprotein pattern, and speculate on the various factors responsible for the striking reduction in cholesterol levels noted in this report.
Abstract: In the accompanying article, Barnard 1 reports data from 4587 adults who attended the residential program at the Pritikin Longevity Center, Santa Monica, Calif, for a period of 3 weeks. During this period, participants consumed a high-complex-carbohydrate, high-fiber, low-fat, and low-cholesterol diet combined with daily aerobic exercise. Total serum cholesterol and low-density cholesterol (LDL-C) values fell substantially, both by 23%; in addition, values of total triglycerides and high-density cholesterol (HDL-C) declined. Barnard suggests that a dietary change such as that employed by the Pritikin Center can markedly improve the lipoprotein pattern. It is interesting to speculate on the various factors responsible for the striking reduction in cholesterol levels noted in this report. These factors probably include: (1) regression to the mean, (2) effects of institutionalization, (3) reduction in dietary saturated fatty acids, (4) reduction in dietary cholesterol, (4) weight loss, and (5) exercise. Each of these factors can be considered briefly.
TL;DR: Combining VLDL and LDL into a common category of atherogenic lipoproteins provides a rational framework for treatment of hypercholesterolemic patients with hypertriglyceridemia and a hydroxymethylglutaryl coenzyme A reductase inhibitor may be the best choice for treatment when both triglyceride and cholesterol levels are elevated.
Abstract: If triglyceride-rich very-low-density lipoproteins (VLDLs) are a vehicle for transporting cholesterol into the arterial wall, they can be equated to low-density lipoproteins (LDLs) in estimating CHD risk and setting targets for therapy. Furthermore, the fate of cholesterol-rich VLDL (VLDL remnants) is similar to that of LDL; that is, both are removed from the circulation via LDL receptors. Thus, combining VLDL and LDL into a common category of atherogenic lipoproteins provides a rational framework for treatment of hypercholesterolemic patients with hypertriglyceridemia. A hydroxymethylglutaryl coenzyme A reductase inhibitor may be the best choice for treatment when both triglyceride and cholesterol levels are elevated, because these agents cause the greatest reduction in VLDL and LDL cholesterol levels. When hypertriglyceridemia is severe, a fibric acid or nicotinic acid is preferable, because these agents are more effective for lowering triglyceride levels and hence for reducing risk for acute pancreatitis.