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Showing papers by "Scott M. Grundy published in 1983"


Journal ArticleDOI
TL;DR: The current data suggest that mevinolin alone ormevinolin plus bile acid depletion (i.e., ileal bypass or colestipol therapy) decreases plasma LDL levels primarily by raising the number of LDL receptors and, thus, enhancing the removal of LDL from plasma.
Abstract: In subject with heterozygous familial hypercholesterolemia (FH), a 50% deficiency of receptors for plasma low density lipoprotein (LDL) impairs the removal of LDL from plasma and produces hypercholesterolemia. In these patients mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, blocks cholesterol synthesis and lowers plasma LDL levels. To determine the mechanism for the LDL-lowering effect, we administered 131I-labeled LDL intravenously to six FH heterozygotes before and during treatment with mevinolin and calculated the apparent fractional catabolic rate (FCR) and synthetic rate for LDL. After mevinolin treatment, the mean plasma LDL-cholesterol level declined from 262 to 191 mg/dl (27% decrease), the mean FCR for 131I-labeled LDL increased from 0.30 to 0.41 pools per day (37% increase), and the mean calculated synthetic rate for LDL-protein did not change significantly. In one of FH heterozygote with an ileal bypass and in another who received colestipol, the addition of mevinolin caused, respectively, a 41% and 60% decrease in plasma LDL levels and a 60% and 100% increase in the FCR for plasma LDL. The contribution of receptor-dependent pathways to the FCR for plasma LDL was estimated in three FH heterozygotes by simultaneous measurements of the FCR for native 131I-labeled LDL and 125I-labeled glucosylated LDL, which does not bind to LDL receptors. Whereas the removal rate for native LDL increased after mevinolin treatment, the removal rate for glucosylated LDL did not change. The current data suggest that mevinolin alone or mevinolin plus bile acid depletion (i.e., ileal bypass or colestipol therapy) decreases plasma LDL levels primarily by raising the number of LDL receptors and, thus, enhancing the removal of LDL from plasma.

526 citations


Journal ArticleDOI
TL;DR: The large, triglyceride-enriched VLDL observed in familial hypertriglyceridemia is compatible with the reported increase in V LDL triglyceride synthesis seen in this disorder and provides further support that they are distinct entities.

311 citations



Journal ArticleDOI
TL;DR: The isopropanol method has been demonstrated to yield consistent data for apoB specific activities in a study of VLDL, IDL, and LDL metabolism.

215 citations


Journal ArticleDOI
TL;DR: To determine the influence of weight reduction on plasma lipoproteins, studies were carried out in 15 nondiabetic patients of varying degrees of obesity and four obese insulin-dependent diabetics and patients underwent three dietary periods.
Abstract: To determine the influence of weight reduction on plasma lipoproteins, studies were carried out in 15 nondiabetic patients of varying degrees of obesity and four obese insulin-dependent diabetics. All studies were carried out on a metabolic ward and patients underwent three dietary periods: Period I, 4 to 5 weeks of weight maintenance in the obese state; Period II, caloric restriction to 1000 kcal/day to a weight loss of within 10% of ideal body weight; and Period III, again weight maintenance for 4 to 5 weeks near ideal body weight. Similar results were obtained for both nondiabetics and diabetics. Many patients had mildly elevated plasma triglycerides in Period I; they fell to the normal range in Period II and remained low in Period III. Total cholesterol levels decreased early in Period II, but levels began to rise near the end of caloric restriction, and in Period III, they were similar to Period I. Low density lipoprotein cholesterol levels followed a pattern similar to that of total cholesterol. High density lipoprotein cholesterol was relatively low in Period I (38 +/- 2 mg/dl +/- SEM); throughout weight loss, levels tended to rise, and in Period III, the average high density lipoprotein cholesterol was significantly higher (46 +/- 2 mg/dl).

128 citations


Journal ArticleDOI
TL;DR: It is found that obese patients have increased turnover of apoLDL, not necessarily reflected by high concentrations of LDL-cholesterol, which may raise the risk for coronary heart disease in obese patients.
Abstract: Turnover rates of the apolipoprotein of low density lipoproteins (apoLDL) and cholesterol balance were determined in six obese men and six control men. The two groups were of similar age and matched for apoLDL concentrations. Levels of plasma total cholesterol in obese patients (209 +/- 14 SEM mg/dl) were similar to controls (225 +/- 17 mg/dl). LDL-cholesterol was numerically but not statistically lower in obese subjects (111 +/- 18 mg/dl) compared to controls (145 +/- 13 mg/dl). Synthetic rates of apoLDL in contrast were higher in obese patients (1450 mg/day) than in controls (934 mg/day) (p less than 0.002). Three factors could explain the similar concentrations of LDL-cholesterol in obese and control subjects, despite overproduction of apoLDL in the obese. First, LDL was diluted into a larger plasma pool in obese patients; second, fractional catabolic rates of apoLDL were somewhat greater in obese men than in controls; and third, obese patients had higher ratios of protein-to-cholesterol in LDL. The production of apoLDL for all patients was not correlated with total body synthesis of cholesterol. The major finding of this study was that obese patients have increased turnover of apoLDL, not necessarily reflected by high concentrations of LDL-cholesterol. This high turnover rate itself may raise the risk for coronary heart disease in obese patients.

109 citations


Journal ArticleDOI
TL;DR: The only significant alteration induced by soy proteins in this study was a reduction of plasma triglycerides when levels were elevated; soy proteins had no discernable effects on the metabolism of cholesterol.

89 citations


Journal ArticleDOI
01 Jan 1983-Diabetes
TL;DR: The mechanism responsible for the observed change in plasma triglyceride levels in normolipidemic type I diabetic patients that occurs with 3 wk of CSII treatment is due to suppression of hepatic VLDL-TG synthesis rather than the result of increased lipoprotein clearance.
Abstract: The effect of continuous subcutaneous insulin infusion (CSII) on very-low-density lipoprotein triglyceride (VLDL-TG) metabolism was studied in seven normolipidemic type I diabetic patients. VLDL-TG transport was determined using 3H-glycerol as an endogenous precursor of VLDL-TG, and the resultant turnover curves were evaluated by multicompartmental analysis. Kinetic studies were performed in the diabetic patients during conventional insulin therapy and again after 3 wk of euglycemia achieved with CSII, and the results were compared with those obtained in 5 age-, weight-, and sex-matched normolipidemic nondiabetic subjects. After 3 wk of CSII, the mean (± SEM) 24-h plasma glucose levels in the diabetic patients decreased from 238 ±15 mg/dl on conventional therapy to 99 ± 11 mg/dl (P < 0.05) on CSII therapy. The total glycosylated hemoglobin levels decreased from 10.2 ± 0.5 to 6.5 ± 0.4%. There was a significant decrease in fasting plasma cholesterol (172 ± 13 mg/dl to 136 ± 4 mg/dl), LDL cholesterol (104 ± 9 mg/dl to 82 ± 4 mg/dl), plasma triglyceride (114 ± 24 mg/dl to 71 ± 9 mg/dl), and VLDL-TG (68 ± 18 mg/dl to 37 ± 5 mg/dl) levels. There was no change in the HDL cholesterol concentration. Results of the kinetic studies in the conventionally treated diabetic patients revealed normal VLDL-TG transport rates and fractional catabolic rates (FCR). CSII caused a marked and significant fall in mean VLDL-TG transport rates (12.2 ± 3.5 to 4.1 ± 0.8 mg/h/kg IW, P < 0.05) to levels below those observed in the nondiabetic subjects (10.2 ± 2.1 mg/h/kg IW, P < 0.05). There was no change in the mean FCR with CSII. These data thus suggest that the mechanism responsible for the observed change in plasma triglyceride levels in normolipidemic type I diabetic patients that occurs with 3 wk of CSII treatment is due to suppression of hepatic VLDL-TG synthesis rather than the result of increased lipoprotein clearance.

85 citations


Journal ArticleDOI
TL;DR: Findings indicate that some patients with CHD have abnormalities in the turnover of apoLDL, even with normal concentrations of LDL; these abnormalities may contribute to accelerated atherosclerosis.
Abstract: The turnover rates of low density lipoprotein-apolipoprotein (apoLDL) were determined in eight men with coronary heart disease (CHD) and seven men matched for age, weight, and plasma lipid levels who were used for controls. The CHD patients were normocholesterolemic (plasma cholesterol = 204 +/- 8 mg/dl sem) as were the control subjects (227 +/- 15 mg/dl). The concentrations of plasma LDL cholesterol and apoLDL were similar for the two groups. In contrast, the synthetic rates of apoLDL were higher in the CHD patients (20.0 +/- 1.8 mg/kg/day) than in the controls (12.9 +/- 1.1 mg/kg/day) (p less than 0.01). The ratios of protein-to-cholesterol in LDL averaged 19% higher in the CHD patients. These patients with CHD maintained normal LDL levels despite an over-production of apoLDL because of an increased capacity for LDL removal; their fractional catabolic rates of apoLDL averaged 43% higher than those of the controls. These findings indicate that some patients with CHD have abnormalities in the turnover of apoLDL, even with normal concentrations of LDL; these abnormalities may contribute to accelerated atherosclerosis.

60 citations


Journal Article
TL;DR: The current results show that one can exploit the normal regulation of receptor synthesis to stimulate the single normal gene in FH heterozygotes to produce an increased number of LDL receptors, and raises the possibility that other genetic diseases may be treated through manipulation of regulatory signals that control the rates of synthesis of gene products.
Abstract: The current results show that one can exploit the normal regulation of receptor synthesis to stimulate the single normal gene in FH heterozygotes to produce an increased number of LDL receptors. This stimulation can be achieved by drugs that inhibit HMG CoA reductase in the liver and by maneuvers that cause bile acid depletion. These two therapeutic approaches are most effective when they are combined. It seems reasonable to speculate that such a profound lowering of plasma cholesterol levels will minimize the development of atherosclerosis in FH heterozygotes. In a broader sense, the success of this regulatory manipulation raises the possibility that other genetic diseases may be treated through manipulation of regulatory signals that control the rates of synthesis of gene products.

56 citations


Journal ArticleDOI
TL;DR: It is indicated that response to reduction in fat content is inconsistent; the majority of patients were responders; others, however, were not.
Abstract: This study was designed to determine effects of reducing intake of total fat and increasing carbohydrate (glucose) on plasma lipoproteins. Eleven men were investigated. They were given two diets for 1 month each. One diet contained 40% of calories as fat with 20% saturated fatty acids, 10% monounsaturates and 10% polyunsaturates. The other diet contained 30% fat with equal amounts of each type of fatty acid. The 10% of fat removed from the latter was replaced by glucose. Six patients had significant reductions of cholesterol in total plasma and low density lipoprotein (LDL) on the 30% fat; for the group as a whole; however, the decrease was not statistically significant. Total triglycerides increased modestly (15%) and high density lipoprotein (HDL)-cholesterol fell significantly (14%) on replacement of 40% fat with 30% fat. Seven patients also were given a 30% fat diet containing fatty acids in the same proportions as in the 40% fat diet. A similar response was noted as when fatty acids were given in equal ratios. This study indicates that response to reduction in fat content is inconsistent. The majority of patients were responders; others, however, were not.

Journal ArticleDOI
TL;DR: The fact that bile acid excretion failed to increase, and actually decreased slightly, suggests that the effect is upon bile Acid synthesis, which is probably physiologically unimportant in normal humans.

Journal ArticleDOI
TL;DR: Modulation of the primary injurious factors through alteration of secondary risk factors is currently the only significant approach to prevention of atherosclerosis.
Abstract: Atherosclerosis is a complex disease that represents the end product of the interaction of many different causative agents. Those that originate external to the arterial wall usually are called primary risk factors. Many other influences, the secondary risk factors, modulate the primary factors. The penetrance of the secondary factors is variable. They can have a major effect in some people but not in others. The idea of risk factor is important because it provides the conceptual framework upon which to build an intervention program for prevention of atherosclerosis. The development of atherosclerosis can be viewed as a two-step process (Table 2). The first is injury to the arterial wall. The second is response to injury. The primary risk factors can be regarded as the injurious agents. Examples are factors causing endothelial damage, influx of plasma lipoproteins, toxic products of smoking, hemodynamic injury of hypertension, and perhaps microvascular injury from diabetes mellitus. The response to injury represents typical pathologic changes--proliferation of smooth muscle cells, mononuclear infiltration, phagocytosis of products of injury, secretion of connective tissue elements, neovascularization, and necrosis. Regulation of these latter processes is poorly understood and is a worthy subject for future research. Modulation of the primary injurious factors through alteration of secondary risk factors is currently the only significant approach to prevention of atherosclerosis. Future investigation may provide more direct ways to prevent or retard atherogenesis, either by more effective modification of primary factors or by reducing the magnitude of response to these factors.

Journal ArticleDOI
TL;DR: The results show preferential transfer or exchange or absorbed phosphatidylcholine into specific subclasses of HDL, corresponding to the subclass previously designated HDL2a and HDL2b.
Abstract: The incorporation of orally administered phospholipid into plasma high-density lipoproteins (HDL) was studied in three subjects. Plasma was analyzed by equilibrium density gradient ultracentrifugation, 5, 6, and 8 h after ingestion of 1.1 g [3H-choline, 14C-dilinoleoyl]phosphatidylcholine. At all time points in all subjects, there was a peak of phosphatidylcholine specific activity in fractions of density approximately 1.10-1.13 g/ml, corresponding to the subclass previously designated HDL2a. There was also a more variable, smaller peak of specific activity of phospholipids in HDL2b (1.063-1.100 g/ml) and in fractions of density approximately 1.19 g/ml. In the 1.10-1.13 fraction, 97 and 71%, respectively, of the 3H and 14C radioactivity were in phospholipids. The 3H/14C ratio was similar in phospholipids of HDL subfractions, the d less than 1.07 fraction, and in the administered phospholipid. The results show preferential transfer or exchange or absorbed phosphatidylcholine into specific subclasses of HDL.

Journal ArticleDOI
TL;DR: In this article, the problem of determining whether or not a particular parameter, or the entire compartmental system, is structural identifiable can be considerably simplified if the system can be decomposed into smaller subsystems in such a way that a parameter is structurally identifiable with respect to the large system if and only if it is Structured Identifiable (SIO) with respect the subsystem in which it is contained.
Abstract: The problem of determining whether or not a particular parameter, or the entire compartmental system, is structural identifiable can be extremely difficult if the number of unknown parameters and the number of compartments is large. However, the problem can be considerably simplified if the system can be decomposed into smaller subsystems in such a way that a parameter is structural identifiable with respect to the large system if and only if it is structural identifiable with respect to the subsystem in which it is contained. The paper offers sufficient conditions under which the desired decomposition can be achieved. The conditions are expressed in terms of the digraph of the system so that they are not difficult to verify. Illustrative examples are provided in terms of application to lipoprotein kinetics.

Journal ArticleDOI
TL;DR: It is suggested that the patients who are at risk of developing gallstones can be better selected by cholesterol crystal analysis of bile samples than by analysis of lipid composition of biles.
Abstract: Lipid composition, cholesterol saturation, and cholesterol crystal formation of gallbladder bile were studied in seven type-IV hyperlipoproteinemic subjects who did not have gallstones. Thereafter, biliary cholesterol solubilization was overloaded, first by clofibrate and then by caloric restriction treatment. Initially increased cholesterol saturation was still increased by both clofibrate and caloric restriction treatment, but none of the subjects developed cholesterol crystals in bile, indicating that they had a mechanism to maintain cholesterol in solution in the bile despite remarkable supersaturation. This suggests that the patients who are at risk of developing gallstones can be better selected by cholesterol crystal analysis of bile samples than by analysis of lipid composition of bile.



Book ChapterDOI
01 Jan 1983
TL;DR: It is found that overproduction of lipoproteins occurs in many different forms of hyperlipidemia, and it may be an underlying defect in these several types.
Abstract: Levels of plasma lipoproteins are regulated by the balance between their production and clearance. Although great attention has been paid to mechanisms for clearance of lipoproteins from plasma, work on factors regulating the production of lipoproteins has been limited. In recents Years, however, our laboratory has become interested in the role of lipoprotein production in the regulation of their levels. This work has been concerned with two major moieties of the plasma lipoproteins, namely, triglycerides and apolipoprotein B (apo B). Triglycerides (TG) are the major lipid constituent of very low density lipoproteins (VLDL), and apo B is the major apoprotein of both VLDL and low density lipoproteins (LDL). Our findings suggest that overproduction of these constituents is an important factor in the development of hyperlipoproteinemia. Of particular interest, we have found that overproduction of lipoproteins occurs in many different forms of hyperlipidemia, and it may be an underlying defect in these several types. The following discussion will consider the spectrum of disorders associated with overproduction of lipoproteins.