Showing papers by "Scott M. Grundy published in 1984"
TL;DR: It is concluded that a genetically determined deficiency of LDL receptors can be largely reversed by liver transplantation, underscoring the importance of hepatic LDL receptors in controlling the plasma level of LDL cholesterol in human beings.
Abstract: A six-year-old girl with severe hypercholesterolemia and atherosclerosis had two defective genes at the low-density-lipoprotein (LDL) receptor locus, as determined by biochemical studies of cultured fibroblasts. One gene, inherited from the mother, produced no LDL receptors; the other gene, inherited from the father, produced a receptor precursor that was not transported to the cell surface and was unable to bind LDL. The patient degraded intravenously administered 125I-LDL at an extremely low rate, indicating that her high plasma LDL-cholesterol level was caused by defective receptor-mediated removal of LDL from plasma. After transplantation of a liver and a heart from a normal donor, the patient's plasma LDL-cholesterol level declined by 81 per cent, from 988 to 184 mg per deciliter. The fractional catabolic rate for intravenously administered 125I-LDL, a measure of functional LDL receptors in vivo, increased by 2.5-fold. Thus, the transplanted liver, with its normal complement of LDL receptors...
406 citations
TL;DR: Obese subjects appeared to be more susceptible to the hyperlipidemic effects of alcohol; whereas 4/6 obese patients developed increased total triglyceride and VLDL-triglyceride concentrations when alcohol was administered, concentrations increased with alcohol administration in only 1/6 lean individuals.
201 citations
TL;DR: Mechanisms for the hypolipidemic action of gemfibrozil were examined in seven patients with hypertriglyceridemia and seven hyperlipidemic patients were studied with and without clofibrate treatment to compare the mechanisms by which these two drugs lower plasma triglyceride levels.
Abstract: Mechanisms for the hypolipidemic action of gemfibrozil were examined in seven patients with hypertriglyceridemia. In addition, seven hyperlipidemic patients were studied with and without clofibrate treatment to compare the mechanisms by which these two drugs lower plasma triglyceride levels. All patients were studied on a metabolic ward. The first month was a control period, followed by one month of either gemfibrozil or clofibrate therapy. During treatment with gemfibrozil, plasma total triglyceride levels decreased by an average of 51%, and triglyceride levels in very low—density lipoproteins (VLDLs) fell by 57%. Transport rates of VLDL triglyceride were determined by multicompartmental analysis following injection of tritiated glycerol as a precursor. Gemfibrozil decreased transport (production) of VLDL triglyceride by an average of 28% and increased the fractional catabolic rate (FCR) of VLDL triglyceride by 92%. Clofibrate reduced plasma total triglyceride values on an average of 32% and VLDL triglyceride values by 38%. In contrast to gemfibrozil, clofibrate did not change transport rates of VLDL triglyceride but increased the fractional catabolic rate of VLDL triglyceride by 35%. Gemfibrozil thus decreased production of VLDL triglycerideandenhanced its clearance, while clofibrate only increased clearance of VLDL triglyceride. On the average, plasma cholesterol levels did not fall during gemfibrozil treatment, but levels of cholesterol in high-density lipoproteins and in low-density lipoproteins increased by 31% and 11%, respectively. The drug produced a 30% increase in fecal excretion of neutral steroids and a 37% decrease in fecal excretion of bile acids. Outputs of total neutral steroids and net cholesterol balance thus remained unchanged. (JAMA1984;251:2241-2246)
158 citations
TL;DR: It is concluded that the LDL lowering action of mevinolin does not appear to require a severe decrease in cholesterol synthesis that might lead to depletion of vital body stores of cholesterol.
Abstract: Patients with heterozygous familial hypercholesterolemia (FH) have a deficiency of receptors for plasma low-density lipoprotein (LDL) that impairs removal of LDL from plasma. In these patients, mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase [mevalonate:NAD+ oxidoreductase (CoA-acylating), EC 1.1.1.88], increases receptors for LDL and decreases LDL concentrations. To determine whether mevinolin also causes severe decreases in total body synthesis of cholesterol, fecal excretions of neutral steroids and acidic steroids were determined in five FH heterozygotes before and during treatment with mevinolin. The drug produced an average decrease in plasma total cholesterol of 23% and in LDL cholesterol of 24%. Mevinolin caused a significant decrease in the output of neutral and acidic steroids in three patients, but it caused no alterations in two others. Changes in fecal output of steroids did not correlate with the degree of lowering of the patients' LDL-cholesterol level. In none of the patients did the output of fecal steroids fall below the values seen in normal subjects studied under similar conditions. One patient had a previous ileal exclusion operation and had a massive output of acidic steroids in the control period; mevinolin therapy caused a slight decrease in excretion of acidic steroids, but the output was still markedly above normal. We conclude that the LDL lowering action of mevinolin does not appear to require a severe decrease in cholesterol synthesis that might lead to depletion of vital body stores of cholesterol.
124 citations
TL;DR: Data show that probucol lowers LDL by increasing its catabolism, which appears to be independent of any changes in metabolism of cholesterol or bile acids.
91 citations
TL;DR: Six male subjects with normal gastroenterologic function were studied to determine the effects of ursodeoxycholic and tauroursodexycholic acid feeding on bile acid synthesis and cholesterol absorption and the percentage of cholesterol absorption was decreased.
90 citations
Journal Article•
72 citations
TL;DR: Failure of diabetic treatment to restore VLDL-TG kinetic parameters to normal suggests that the hypertriglyceridemia was due not only to diabetes mellitus but also to an additional abnormality affecting lipoprotein metabolism.
Abstract: We examined the effect of diabetic control on very low-density lipoprotein-triglyceride (VLDL-TG) metabolism in six patients with type II (noninsulin-dependent) diabetes mellitus and marked hypertriglyceridemia. VLDL-TG transport was determined using 3H-glycerol as an endogenous precursor of VLDL-TG, and the resultant kinetic data were evaluated by multicompartmental analysis. Studies were performed in the hypertriglyceridemic diabetic subjects during poor diabetic control and again after 3 months of diabetic treatment, and the results were compared to studies in nondiabetic normolipidemic subjects and nondiabetic subjects with familial forms of hypertriglyceridemia. In the poorly controlled diabetics, mean VLDL-TG synthesis was threefold higher than in the normolipidemic subjects, and the mean fractional catabolic rate (FCR) of VLDL-TG was only one-third of the normals. With diabetic treatment, plasma triglyceride levels fell by more than 50%, but remained fourfold higher than the normals. This was associated with a decrease in mean VLDL-TG synthesis to a level similar to that observed in the genetic hyperlipidemic subjects, but still 2.6-fold higher than the normals. In addition, the mean FCR rose after diabetic control to a level slightly above that of the genetic hyperlipidemic subjects, but remained less than one-half of the normal value. However, the response of VLDL-TG kinetics to diabetic treatment was not uniform. In four subjects, control of hyperglycemia ameliorated the hypertriglyceridemia primarily by decreasing VLDL-TG overproduction. In the other two subjects, diabetic treatment had a greater effect on the FCR than an overproduction of VLDL-TG. Thus, in this select group of diabetic, hypertriglyceridemic subjects, poor diabetic control contributed to both VLDL-TG overproduction and low FCRs. Failure of diabetic treatment to restore VLDL-TG kinetic parameters to normal suggests that the hypertriglyceridemia was due not only to diabetes mellitus but also to an additional abnormality affecting lipoprotein metabolism. Furthermore, the finding of two types of kinetic response to diabetic treatment suggests that underlying presumably familial abnormalities of lipoprotein transport are important in determining the effect of diabetes on VLDL-TG metabolism.
64 citations
Journal Article•
63 citations
TL;DR: It is suggested that a decrease in production of LDL is a major factor in the lowering of LDL following inhibition of cholesterol absorption; however, an increase in clearance rates may occur in some patients.
Abstract: The mechanisms for the hypocholesterolemic actin of neomycin were examined in six patients with various levels of plasma total cholesterol and triglycerides. All patients were studied on a metabolic ward. The first period of 6 weeks was for control. Thereafter, neomycin (1.5 g/day) was started, and the patients were readmitted for another 6-week period after 2 to 3 months of treatment with the drug. Cholesterol balance studies showed that neomycin increased fecal excretion of neutral steroids by an average of 45%; the drug also inhibited absorption of exogenous cholesterol by an average of 44%. During treatment with neomycin, the plasma total cholesterol fell by an average of 20%, low density lipoproteins (LDL) fell by 25%, and high density lipoproteins, by 16%. Neomycin did not change plasma triglyceride levels. Turnover of the apoprotein of LDL (apoLDL) was measured following injection of 125I-apoLDL. Neomycin decreased synthesis of apoLDL by 28%. The decrease in plasma apoLDL level was correlated positively with the decrease in apoLDL synthetic rate. The effect of the drug on clearance of LDL was less constant; four of six patients had an increase in fractional clearance rates of apoLDL, but the change for the whole group was not statistically significant. These data suggest that a decrease in production of LDL is a major factor in the lowering of LDL following inhibition of cholesterol absorption; however, an increase in clearance rates may occur in some patients.
59 citations
TL;DR: This work has shown that the development of isotopic tracer techniques, particularly multicompartmental analysis, has facilitated the elucidation of quantitative defects of lipoprotein transport responsible for other dyslipoproteinemias.
TL;DR: LLB may not prove to be a better indicator of coronary risk in normolipidemic people, but LDL-apoB could be a superior predictor of risk in HTG patients.
01 Jan 1984
TL;DR: Lipoprotein overproduction can give rise to multiple lipoprotein phenotypes in a single family, and specific therapy of hyperlipoproteinemia should be directed toward correcting these metabolic defects.
Abstract: Most forms of hyperlipoproteinemia are the result of at least 1 of 4 basic defects of lipoprotein metabolism Hypercholesterolemia is most commonly due to decreased activity of receptors for low-density lipoproteins (LDL) A deficiency of LDL receptors can be caused by either a genetic defect in the structure of the receptor or metabolic suppression of receptor synthesis by genetic factors or dietary saturated fatty acids and cholesterol An elevation of triglycerides in chylomicrons or very low density lipoproteins (VLDL) can be secondary to a reduced activity of lipoprotein lipase, and an increase in the catabolic remnants of these lipoproteins can be due to an abnormal isoform of apolipoprotein E, the apolipoprotein that mediates hepatic uptake of lipoprotein remnants Finally, hepatic overproduction of VLDL can produce hypertriglyceridemia, or if there is a concomitant defect in clearance of lipoproteins, an accentuated increase of VLDL, remnants or LDL will occur Thus, lipoprotein overproduction can give rise to multiple lipoprotein phenotypes in a single family Specific therapy of hyperlipoproteinemia should be directed toward correcting these metabolic defects
TL;DR: It is demonstrated that in most patients with type 5 HLP there is a dual defect in TG metabolism--overproduction of VLDL TGs and a clearance defect for TG-rich lipoproteins.
Abstract: Transport of very-low-density lipoprotein (VLDL) triglycerides (TGs) were studied in eight patients with type 5 hyperlipoproteinemia (HLP). Results were compared to those from patients with type 4 HLP. Type 4 patients had either overproduction of VLDL TGs (nine patients) or defective clearance of VLDL TGs (eight patients). Patients with type 5 HLP were found to have increased production rates of VLDL TG, but also reduced fractional catabolic rates of VLDL TGs. Synthesis rates of VLDL TGs in type 5 were similar to those in type 4 patients with overproduction of VLDL TGs. The mean fractional catabolic rate in patients with type 5 HLP also were similar to those of type 4 patients with defective clearance. This study demonstrates that in most patients with type 5 HLP there is a dual defect in TG metabolism—overproduction of VLDL TGs and a clearance defect for TG-rich lipoproteins. (JAMA1984;251:2542-2547)
TL;DR: The National Cooperative Gallstone Study was a double-masked trial conducted to determine the efficacy and safety of chenodeoxycholic acid (chenodiol) for dissolution of cholesterol gallstones, indicating that development of unsaturated bile was a major factor associated with gallstone dissolution.
Abstract: The National Cooperative Gallstone Study was a double-masked trial conducted to determine the efficacy and safety of chenodeoxycholic acid (chenodiol) for dissolution of cholesterol gallstones. Patients with radiolucent gallstones were randomly allocated to either a high dose (750 mg/d, n = 305) or low dose (375 mg/d, n = 306) of chenodiol or placebo (n = 305) administered for 2 yr. Specimens of gallbladder bile were obtained for biliary lipid analysis on 50% of all white obtained for biliary lipid analysis on 50% of all white patients at base line and after 3-mo therapy, on 45% at 12 mo, and on 36% at 24 mo. Among these specimens, 20% were inadequate for analysis. For analysis of data, available values during therapy were averaged up to time of dissolution, study exit, or study termination. In the high-dose group, percent chenodiol (molar percent of all bile acids) increased markedly and remained high during the 2 yr of follow-up. Also, molar percent cholesterol decreased significantly and remained low during the 2 yr of follow-up. In the low-dose group, percent chenodiol increased and remained significantly increased. Percent cholesterol saturation decreased at 3 mo, but at 24 mo it was not different from that in the placebo group, suggesting a physiological adaptation to the low dose by 2 yr. 79% of patients on high dose had greater than 70% chenodiol. Among these, half showed unsaturated bile (less than 100% cholesterol saturation) while the remainder were supersaturated; in the former group with unsaturated bile, 23% had complete dissolution and 51% had partial (greater than 50% reduction in stone size) or complete dissolution. In contrast, those with over 70% chenodiol and supersaturated bile had only 5% complete dissolution. Thus, development of unsaturated bile was a major factor associated with gallstone dissolution. The data also indicate that values for percent cholesterol saturation were a better predictor of gallstone dissolution than molar percent chenodiol, although a high percent chenodiol usually was required to obtain unsaturation.
TL;DR: In this article, the authors studied the relationship between the cycles in the graph of a compartmental system and the modes of the impulse response function associated with an input-output experiment and showed that the system contains a cycle of length 3 or longer and that the length of the longest cycle is at least π /tan -1 [¦ v ¦/( ϱ - μ )].
Abstract: The paper concerns the relationship between the cycles in the graph of a compartmental system and the modes of the impulse response function associated with an input-output experiment. Suppose that there is at least one oscillatory mode, e μt cos( vt - α ). Let e ϱt be the slowest mode. The main result is that the system contains a cycle of length 3 or longer and that the length of the longest cycle is at least π /tan -1 [¦ v ¦/( ϱ - μ )]. The paper also deals with the problem of estimating the cycle length from discrete data.
TL;DR: In this article, a condensation model is proposed to summarize a large model by presenting a smaller one to emphasize certain salient properties of the larger model, such as the mean residence times through the blocks.
Abstract: Suppose that the compartments of a compartmental model are separated into blocks (sets of compartments). In general, the blocks can not be regarded as compartments but it may be possible to construct a “condensation model,” the compartments of which correspond to the blocks, in such fashion so as to retain certain salient properties of the blocks. Condensation is a way of formally summarizing a large model by presenting a smaller one to emphasize certain characteristics of the larger model. Suppose that the parameters to be retained are the mean residence times through the blocks; this paper deals with the construction of the condensation model, the properties of the condensation model, and the possible applications of condensation to data analysis, particularly in regard to lipoprotein kinetics.