Showing papers by "Scott M. Grundy published in 1979"

Transport of Very Low Density Lipoprotein Triglycerides in Varying Degrees of Obesity and Hypertriglyceridemia

Abstract: Measurements of transport of triglycerides (TG) in very low density lipoproteins (VLDL) were carried out in 59 patients by injection of radioactive glycerol, determinations of specific activities of VLDL-TG for 48 h thereafter, and treatment of the data by multicompartmental analysis. The patients were divided into three groups: normal weight (89-120% ideal weight), mildly obese (120-135% ideal weight), and markedly obese (135% ideal weight). They had varying levels of VLDL-TG ranging from normal to markedly elevated. In many subjects, there was a positive correlation between concentrations and transport of VLDL indicating that overproduction of VLDL-TG contributed to hypertriglyceridemia. In others, and particularly in several markedly obese subjects, transport rates were greatly increased without significant hypertriglyceridemia, suggesting that they had enhanced capacity to clear TG. In all groups, however, there were patients whose degree of hypertriglyceridemia seemed out of proportion to their transport rates. This finding and the fact that many patients have increased secretion of VLDL-TG without elevated plasma TG suggests that both overproduction of VLDL-TG and insufficient enhancement of clearance contributed to the development of hypertriglyceridemia. The data showed a poor correlation between transport rates determined by our multicompartment analysis and single-exponential analysis used previously by other investigators (r = 0.46); this comparison was not improved by segregating patients according to their degree of obesity. Although two conversion pathways (fast and slow synthetic paths) were required to fit the data, there was no correlation between transport rates and the ratio of the two pathways. Also, despite the known pathway of conversion of VLDL to low density lipoprotein, no correlation was found between VLDL-TG transport rates and estimated low density lipoprotein-cholesterol concentrations.

Metabolic Studies in Familial Hypercholesterolemia: EVIDENCE FOR A GENE-DOSAGE EFFECT IN VIVO

Abstract: To investigate the gene-dosage effect in familial hypercholesterolemia (FH), metabolic studies were conducted in a group of well-characterized patients with either heterozygous (n = 7) or homozygous (n = 7) FH and the results were compared to those obtained in normal subjects (n = 6). The turnover of 125I-labeled low-density lipoprotein (LDL) was measured in all of the normals, all but one of the FH heterozygotes, and in all of the homozygotes. Chemical cholesterol balance was performed simultaneously with the 125I-LDL turnover in all seven of the homozygotes. With regard to 125I-LDL turnover, FH homozygotes, who possess two doses of the mutant FH gene, exhibited a threefold increase in the rate of apoLDL synthesis while the fractional catabolic rate (FCR) for the apoprotein was only about one-third of normal. Heterozygotes, who have only one dose of the mutant FH gene, exhibited intermediate values for both parameters; that is, the FCR was two-thirds of normal and the apoLDL synthetic rate was 1.7-fold greater than normal. The data indicate that the single gene defect in FH produces two distinct abnormalities of LDL metabolism: (a) an increase in the synthetic rate for apoLDL and (b) a decrease in the efficiency of apoLDL catabolism. Both defects are more severe in FH homozygotes than in heterozygotes. The FCR for apoLDL in the homozygotes appeared to be fixed at 17%/d whereas the plasma LDL level varied about twofold. These findings suggest that the twofold variation in plasma LDL levels observed in these seven patients is caused by variation in the plasma apoLDL synthetic rates. Consistent with this conclusion was the finding that the correlation between the plasma LDL level and the apoLDL synthetic rates in the seven FH homozygotes was 0.943. The rate of total body cholesterol synthesis determined by chemical cholesterol balance did not appear to clearly differ between normals and patients with either one or two mutant FH genes. Two of the youngest FH homozygotes exhibited cholesterol overproduction but the other five did not. No consistent abnormality of bile acid metabolism was observed in these patients. Because the daily plasma flux of cholesterol on LDL is about threefold greater than the amount of cholesterol produced per day, a significant amount of the cholesterol liberated from LDL degradation must be reused.

Kinetic model for production and metabolism of very low density lipoprotein triglycerides. Evidence for a slow production pathway and results for normolipidemic subjects

Abstract: A model for the synthesis and degradation of very low density lipoprotein triglyceride (VLDL-TG) in man is proposed to explain plasma VLDL-TG radioactivity data from studies conducted over a 48-h interval after injection of glycerol labeled with 14C, 3H, or both. The curve describing the radioactivity of plasma VLDL triglycerides reaches a maximum at about 2 h, after which the decay is biphasic in all cases; the late curvature becoming evident only after 8--12 h. To fit the complex curve, it was necessary to postulate two pathways for the incorporation of plasma glycerol into VLDL-TG, one much slower than the other. A process of stepwise delipidation of VLDL in the plasma compartment, previously proposed for VLDL apoprotein models, was also necessary. Predicted VLDL-TG synthesis rates calculated with this model can differ significantly from those based on experiments of shorter duration in which the slow VLDL-TG component is not apparent. The results of these studies strongly support the interpretation that the late, slow component of the VLDL-TG activity curve is predominantly due to the slowly turning-over precursor compartment in the conversion pathway and is not due either to a slow compartment in the labeled precursor, plasma free glycerol, or to an exchange of plasma VLDL-TG with an extravascular compartment. It also cannot, in these studies, be attributed to a slowly turning-over VLDL-TG moiety in the plasma. The model was tested with data from 59 studies including normal subjects and patients with obesity and(or) various forms of hyperlipoproteinemia. Good fits were obtained in all cases, and the estimated parameter values and their uncertainties for 13 normolipemic nonobese subjects are presented. Sensitivty testing was carried out to determine how critical various parameter estimations are to the assumptions introduced in the modeling.

Effects of sucrose polyester on cholesterol metabolism in man.

Abstract: Sucrose polyester (SPE) is a nonabsorbable, fat-like material that has been shown to lower plasma cholesterol levels in man and that has a high degree of patient acceptability. This study was carried out to examine further its effects on lipid metabolism. We have investigated the action of feeding SPE on plasma levels of cholesterol, triglycerides, and fatsoluble vitamins, on cholesterol absorption, excretion and synthesis, and on biliary lipid composition. Eleven normolipidemic, overweight subjects were studied on the metabolic ward. The design consisted of a 6-wk control period (weight loss at 1000 cal/day) and a 6-wk period of SPE supplementation (also with 1000 cal/day). SPE was tolerated well by all patients; although each patient experienced some degree of increased frequency of stools during the test period, none averaged more than one stool per day during SPE treatment. SPE feeding caused an overall mean reduction in plasma cholesterol of 6.8% beyond the 20% reduction caused by weight loss and low-cholesterol diet alone. Of the 11 patients, 6 had a mean decrease in plasma cholesterol of 12.5%, while 5 did not show a reduction on SPE. Plasma triglyceride levels were reduced initially by 13% during weight loss, and the addition of SPE caused no further reduction. There was no consistent effect on plasma levels of Vitamin A; Vitamin E levels were reduced by 24%. SPE diminished percent cholesterol absorption in every patient tested (control = 38%; SPE feeding = 17%), and there was an overall net increase in neutral sterol excretion (control = 506 mg/day, SPE feeding = 724 mg/day). Bile acid excretion similarly increased (control = 225 mg/day, SPE feeding = 376 mg/day). Percent saturation of gallbladder bile was not adversely affected by sucrose polyester feeding during weight loss.

Metabolic Studies in an Unusual Case of Asymptomatic Familial Hypobetalipoproteinemia with Hypoalphalipoproteinemia and Fasting Chylomicronemia

Abstract: A new kindred with asymptomatic hypobetalipoproteinemia is reported. The proband, age 67, differs from previously described cases in several respects: (a) unusually low levels of low density lipoprotein (LDL) cholesterol (4-8 mg/dl); (b) normal triglyceride levels; (c) low levels of high density lipoprotein; (d) mild fat malabsorption; and (e) a defect in chylomicron clearance. On a high-carbohydrate diet his plasma triglyceride levels, instead of rising, actually fell. Turnover of triglycerides in very low density lipoproteins (VLDL) was low (2.8 mg/kg per h). Fractional catabolic rate of LDL protein was just above the normal range (0.655/d) but net turnover was <10% of normal (0.65 mg/kg per d). The half-life of his chylomicrons was 29 min, five times the normal value. Postheparin lipoprotein lipase activity was normal and apolipoprotein C-II, the activator protein for lipoprotein lipase, was present and functional. Apolipoprotein C-III(1), however, was not detected in the VLDL fraction, a finding previously reported in patients with abetalipoproteinemia. Fecal excretion of cholesterol was almost twice normal; total sterol balance was increased by congruent with40%. The unusual features in the proband that distinguish him from previously described cases and from his affected first-degree relatives suggested that, in addition to the basic gene defect affecting LDL metabolism, he might have a second abnormality affecting clearance of chylomicrons and VLDL. The ratio of apolipoprotein E(3) to E(2) in his VLDL fraction was 0.93, just below the lower limit of normal, suggesting heterozygosity for E(3) deficiency. Whether or not this contributes to his hypertriglyceridemia remains to be established.

Elevated Cholesterol and Bile Acid Synthesis in a Young Patient with Homozygous Familial Hypercholesterolemia

Abstract: Cholesterol balance studies were carried out twice in a young male patient with homozygous familial hypercholesterolemia. At 13 mo, cholesterol balance in this patient averaged 31.3 mg/kg per d, and bile acid excretion was 12.0 mg/kg per d; at 3 yr, results were similar, 27.3 and 15.5 mg/kg per d for cholesterol balance and bile acids, respectively. A normal boy of 3 yr was also studied for comparison with the second study in our patient. Cholesterol balance and bile acid outputs in the normal child were 11.5 and 3.3 mg/kg per d, respectively. Thus, in comparison with the normal child, the patient with homozygous familial hypercholesterolemia had a marked increase in synthesis of cholesterol and bile acids. Although synthesis of bile acids was high in this patient, the fraction of newly synthesized cholesterol converted into bile acids (40-56%) was in the normal range; this suggests that the enhanced output of bile acids was secondary to an increased synthesis of cholesterol and not to malabsorption of bile acids, which likely would have produced a higher fractional conversion. Although our patient has been studied at a younger age than any reported in the literature, two similar children 5 and 6 yr of age were also observed to have elevated cholesterol synthesis. This finding contrasts with those in older children with the homozygous as well as heterozygous forms of this disease who appear to have normal synthesis of cholesterol and bile acids. Therefore, increased synthesis of cholesterol seems to be characteristic of early homozygous familial hypercholesterolemia, and may be a manifestation of a loss of feedback inhibition of cholesterol synthesis secondary to an absence of specific cell-surface receptors for low density lipoproteins. However, as children with this disease grow older, other mechanisms may come into play to restore cholesterol synthesis to normal levels.

Normocholesterolemic dysbetalipoproteinemia with xanthomatosis.

Abstract: A patient is described who has marked palmar xanthomatosis associated with a normal concentration of plasma cholesterol. Analysis of xanthomas revealed them to contain large quantities of cholesterol with both intra- and extracellular lipids. Examination of plasma lipoproteins showed them to be consistent with a pattern of dysbetalipoproteinemia (Type III hyperlipoproteinemia). VLDL had β-mobility on electrophoresis, a high cholesterol/triglyceride ratio, and increased apoprotein B. However, arginine-rich apoprotein was not increased in VLDL, in contrast to hypercholesterolemic patients with the Type III pattern. Nevertheless, the E3 subfraction of the arginine-rich apoprotein was virtually absent, which is characteristic of dysbetalipoproteinemia. Cholesterol and bile acid synthesis were in the normal range. Thus, of particular interest was the development of severe xanthomatosis without hypercholesterolemia in this patient. Therefore, tissue accumulation of cholesterol was apparently the result of a qualitative abnormality in lipoproteins and not due to an excess of plasma cholesterol.

Effects of Diets and Drugs on Biliary Cholesterol Secretion in Man

Abstract: Cholesterol gallstones in human beings are frequently associated with supersaturated bile, i.e., bile that contains more cholesterol than can be solubilized by the bile acids and/or phospholipid content (1). Early studies on the mechanism of formation of supersaturated bile have shown that many patients with supersaturated bile have reduced pools of bile acids (2–3). Although a deficiency of bile acids in the enterohepatic circulation (EHC) therefore was postulated to be the cause of supersaturated bile, a somewhat different mechanism has been reported in American Indian women who have an extremely high incidence of cholesterol gallstones. Grundy, Metzger, and Adler (4) showed that Indian women with stones have two abnormalities leading to production of supersaturated bile: not only were bile acids secreted at a reduced rate by the liver, but also, outputs of biliary cholesterol were increased. Therefore, production of supersaturated bile in Indian women with gallstones was due to a combined defect in sterol metabolism. Furthermore, Grundy, et al (5) reported that increased hepatic secretion of cholesterol was the only detectable defect in production of supersaturated bile in young white women with cholesterol gallstones.

Biliary lipids, gallstones and treatment of hyperlipidaemia.

Abstract: A number of factors are thought to increase the risk for cholesterol gallstone formation. These have recently been discussed in some detail by Bennion & Grundy [l] , and their general categories include age, sex, race, disease, body weight, diets, and drugs.”The incidence of gallstones increases with age in both sexes, but stones are more common in women than men, and the risk in women appears to be accentuated by pregnancy and oral contraceptives. The frequency of gallstones is particularly high in several races or geographic regions (e.g. American Indians, South America, and northern Europe). Cholesterol stones are more common in patients with ileal disease and resection, in cystic fibrosis with pancreatic insufficiency, in hypertriglyceridaemia and in obesity. The increased incidence in obesity may be related to a high caloric intake, but the risk in obese patients undergoing weight reduction still appears to be high. Finally, in recent years, the question has arisen whether certain diets or drugs used in treatment of hyperlipidaemia should not be added to the list of risk factors for cholesterol stone formation. In most of the above conditions an increased risk for cholelithiasis can be linked directly to the occurrence of supersaturated bile, that is, bile containing more cholesterol than can be held in solution by the polar lipids of bile-bile acids and lecithin. Defects causing supersaturated bile are variable and depend on the condition under consideration. For example, obesity, increased caloric intake, and hypertriglyceridaemia cause high outputs of biliary cholesterol whereas ileal disease, caloric restriction, and possibly estrogenic hormones produce a deficiency of bile acids. The possibility that diets and drugs used in treatment of hyperlipidaemia may cause cholesterol gallstones has received increasing attention in the past few years, since induction of significant alterations in lipid or bile acid metabolism by these agents could lead to formation of supersaturated bile and stone development. Many patients with hyperlipidaemia are obese and thus are doubly at risk for gallstone formation. Weight reduction, which is usually considered to be the first line of therapy for their hyperlipidaemia, may cause bile to become more supersaturated and thereby heighten the risk even more. As we have shown recently [2], the administration of chenodeoxycholic acid (CDCA) during caloric restriction in obese subjects will prevent formation of supersaturated bile and thus should protect against gallstone formation. Further studies are needed,

Cholesterol Moderately the Liver and Bile Acid Metabolism in Advanced, Stable Cirrhosis of

Abstract: Bile acid and lipid metabolism were studied in a metabolic ward in 8 patients with moderately advanced, but stable alcoholic cirrhosis, and in 17 control subjects of comparable age and weight. Patients with biopsy-proved cirrhosis were well nourished and had neither ascites nor encephalopathy. Routine liver function tests were normal apart from elevated gamma-glutamyl transpeptidase and significant BSP retention. However, concentrations of serum bile acids and excretion of urinary bile acids were elevated. Their pool sizes and hepatic secretion rates of bile acids were somewhat reduced, but not markedly so, as reported for patients with far-advanced cirrhosis. Also, in contrast to patients with more advanced cirrhosis, our patients did not show a marked reduction of either cholate or deoxycholate in the bile acid pool. Despite relatively low pools of bile acids, percent saturation of fasting gallbladder bile with cholesterol and hepatic secretion of cholesterol were similar to those of control subjects; this lack of an increased saturation in cirrhotics appeared to be due to a greater coupling of cholesterol to phospholipids and bile acids at low outputs of bile acids than found