Showing papers by "Scott M. Grundy published in 1987"

Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding

Abstract: Previous in vivo turnover studies suggested that retarded clearance of low density lipoproteins (LDL) from the plasma of some hypercholesterolemic patients is due to LDL with defective receptor binding. The present study examined this postulate directly by receptor binding experiments. The LDL from a hypercholesterolemic patient (G.R.) displayed a reduced ability to bind to the LDL receptors on normal human fibroblasts. The G.R. LDL possessed 32% of normal receptor binding activity (approximately equal to 9.3 micrograms of G.R. LDL per ml were required to displace 50% of 125I-labeled normal LDL, vs. approximately equal to 3.0 micrograms of normal LDL per ml). Likewise, the G.R. LDL were much less effective than normal LDL in competing with 125I-labeled normal LDL for cellular uptake and degradation and in stimulating intracellular cholesteryl ester synthesis. The defect in LDL binding appears to be due to a genetic abnormality of apolipoprotein B-100: two brothers of the proband possess LDL defective in receptor binding, whereas a third brother and the proband's son have normally binding LDL. Further, the defect in receptor binding does not appear to be associated with an abnormal lipid composition or structure of the LDL: the chemical and physical properties of the particles were normal, and partial delipidation of the LDL did not alter receptor binding activity. Normal and abnormal LDL subpopulations were partially separated from plasma of two subjects by density-gradient ultracentrifugation, a finding consistent with the presence of a normal and a mutant allele. The affected family members appear to be heterozygous for this disorder, which has been designated familial defective apolipoprotein B-100. These studies indicate that the defective receptor binding results in inefficient clearance of LDL and the hypercholesterolemia observed in these patients.

Fatty acid profiles and sensory and carcass traits of tissues from steers and swine fed an elevated monounsaturated fat diet.

Abstract: Twelve Angus X Hereford steers were assigned to either a control high-energy diet or a test diet consisting of 20% rapeseed at the expense of 20% corn. Twelve pigs were allotted to a control diet and two test diets containing either 10 or 20% canola oil (CO). Both CO and oil in the rapeseed contained 60 to 64% oleic acid. Cattle fed rapeseed exhibited little effect from the diet due to apparent indigestibility of the rapeseed. Total saturated fatty acids decreased from 40% in adipose tissue of the control pigs to 15% in the 20% CO-fed pigs. The ratio of monounsaturated to saturated fatty acids (M/S) increased from 1.19 in adipose tissue from control pigs to 3.63 with the addition of 20% CO to the diet. In muscle, the M/S ratio increased from 1.21 in control pigs to 2.46 in the 20% CO treatment group. The percentage of the saturated fatty acids in muscle decreased from 42% in the control to 23% in the 20% CO treatment. Significant increases in "oiliness" and decreases in fat firmness were observed when increasing levels of canola oil were fed. Sensory traits, cooking loss and shear-force values of pork chops were similar among treatment groups. In conclusion, monounsaturated fatty acid content can be elevated substantially in pork without adversely influencing the quality of the meat, thus producing a product perceived to be more healthful by the consumer.

Treatment of Primary Moderate Hypercholesterolemia With Lovastatin (Mevinolin) and Colestipol

Abstract: The introduction of inhibitors of cholesterol biosynthesis offers a new approach to treatment of hypercholesterolemia. One such agent, lovastatin (formerly, mevinolin), causes significant reductions in plasma cholesterol levels. This action can be enhanced by bile acid sequestrants. In this study, lovastatin and colestipol hydrochloride together were administered to ten patients with primary moderate hypercholesterolemia. Compared with a control period, the combined-drug therapy caused a 36% reduction in plasma total cholesterol level, a 48% decrease in low-density lipoprotein (LDL) cholesterol level, and a 17% increase in high-density lipoprotein cholesterol level. The reduction in LDL cholesterol level was due to three factors: (1) a 27% decrease in the production rate of LDL, (2) a 20% increase in fractional catabolic rate of LDL, and (3) a 15% depletion of cholesterol in LDL particles. This major reduction in LDL cholesterol level produced by combined-drug therapy may be valuable for prevention of coronary heart disease in high-risk patients with primary moderate hypercholesterolemia. ( JAMA 1987;257:33-38)

Integrated study of low density lipoprotein metabolism and very low density lipoprotein metabolism in non-insulin-dependent diabetes.

Abstract: The metabolisms of VLDL, IDL, and LDL and their interconversions have been studied in ten obese untreated male Pima Indian diabetics compared to 16 age-, sex-, and weight-matched nondiabetics. VLDL was elevated in the diabetics and had abnormal composition, as indicated by a significantly higher ratio of triglyceride/apo B. Fractional catabolic rates for both VLDL apoB and VLDL triglyceride were lower in diabetics, and diabetics had increased production of VLDL triglyceride but not VLDL apoB compared to obese nondiabetics. A higher proportion of VLDL apoB was removed without conversion to LDL in diabetics. LDL cholesterol and apoB were higher in diabetics, but production of LDL apoB was not different from nondiabetics. Fractional catabolic rate for LDL apoB, however, was significantly lower in the diabetics. The data indicate that the triglyceride-rich VLDL in non-insulin-dependent diabetics are less readily converted to LDL, whereas the elevated LDL in this group of diabetics is due to impaired clearance. Thus, decreased conversion of VLDL to LDL and impaired LDL clearance are two opposing phenomena which may influence the LDL concentration of diabetics in either direction. Thus, despite minimal changes in LDL concentration, there are multiple defects in the metabolism of LDL in non-insulin dependent diabetes which may contribute to the increased atherogenesis in this disorder.

Cardiovascular and risk factor evaluation of healthy American adults. A statement for physicians by an Ad Hoc Committee appointed by the Steering Committee, American Heart Association.

Abstract: Cardiovascular disease is the major cause of death in American adults. The chief form of cardiovascular disease is coronary heart disease (CHD). Prevention of CHD depends on the identification of risk factors in asymptomatic individuals. The American Heart Association recommends that all adults be examined periodically for the presence of silent cardiovascular disease and coronary risk factors. The major risk factors for CHD are smoking, high blood pressure, and high blood cholesterol. Additional factors associated with CHD are high blood triglycerides, reduced levels of high-density lipoproteins, diabetes mellitus, obesity, sedentary lifestyle, and certain behavioral characteristics. Available data suggest that the predominance of CHD among Americans can be attributed to these risk factors, and increasing evidence indicates that appropriate modification of these factors will markedly reduce coronary risk. The purpose of this report is to identify the risk factors, indicate their relation to coronary disease, and recommend an approach to their detection in adults during periodic health examinations.

Dietary fatty acid effects on T-cell-mediated immunity in mice infected with mycoplasma pulmonis or given carcinogens by injection.

Abstract: To test whether or not diets enriched in w-6 polyunsaturated fatty acids are significantly immunosuppressive, B10.D2, DBA/2, and C3B6F1 mice were fed diets enriched for fatty acids: linoleic (POLY), oleic (MONO), palmitic (SAT), or eicosapentanoic (FISH). The B10.D2 and DBA/2 mice were given injected methylcholanthrene several weeks later, and immune studies were performed several months after carcinogen treatment. In conventional quarters, DBA/2 fed the POLY diet survived poorly, and many were infected with Mycoplasma pulmonis, even if given the vehicle, tractinoin, only. B10.D2 mice survived well unless on the POLY diet and given methylcholanthrene. Nevertheless, only mice on the POLY diet were significantly immunosuppressed, and only T-cell-mediated cutaneous sensitivity reactions were affected. Antibody, natural killer cell, and natural cytotoxic cell responses were not influenced by the diets. The C3B6F1 mice were assessed for immune functions prior to carcinogen (ethylnitrosourea) instillation into the trachea, and no immunosuppression was detected. After instillation, mice on the POLY and MONO diets were suppressed for T-cell cutaneous responses. Deliberate infection with Mycoplasma pulmonis resulted in suppressed cutaneous T-cell responses in the POLY group of C3B6F1 mice, and aspirin partially reversed the immunosuppression. Mice on the FISH diet were resistant to immunosuppression. It is tentatively concluded that diets rich in w-6 polyunsaturated diets, while not directly immunosuppressive, do predispose animals to suppression of certain T-cell-mediated immune responses. This immunosuppression can be "triggered" by infection and/or by exposure to carcinogens.

Low-density lipoprotein metabolism in cerebrotendinous xanthomatosis

Abstract: Cerebrotendinous xanthomatosis (CTX) is a rare disorder characterized by a defect in conversion of cholesterol into bile acids, increased plasma levels of cholestanol, and accumulations of sterols in tendons, brain, and coronary arteries. Despite the presence of tendon xanthomas, patients with CTX frequently have low levels of plasma cholesterol and low density lipoproteins (LDL). The mechanisms for a low LDL are not understood. The present study, therefore, was carried out to examine the metabolism of LDL in a 58-year-old black man with CTX. This particular patient had an LDL-cholesterol in the mid-normal range (149 +/- 6 mg/dL). Nonetheless, his fractional catabolic rate (FCR) for LDL-apolipoprotein (apo-LDL) was 0.45 pools/d, which was increased compared to 15 aged-matched men (FCR, 0.30 +/- 0.01 pools/d). His production rate for apo-LDL (18.5 mg/kg-d) also was increased compared to those of middle-aged men (13.5 +/- 2.5 mg/kg-d). Since the underlying defect in CTX can be reversed by administration of chenodeoxycholic acid (chenodiol), the patient was treated with chenodiol (250 mg 4X daily), and measurements of LDL kinetics were repeated. During chenodiol therapy, his LDL-cholesterol concentration rose significantly to 165 +/- 12 mg/dL; his FCR for apo-LDL fell to 0.29 pools/d; and his production rate of apo-LDL declined to 14.4 mg/kg-d. We postulate that chenodiol suppressed the excessive synthesis of cholesterol and bile acids, which had two effects. It curtailed both the overproduction of LDL and the excessive synthesis of LDL receptors, the latter being responsible for the high FCR of apo-LDL in the untreated state.

Increased catabolism of VLDL-apolipoprotein B and synthesis of bile acids in a case of hypobetalipoproteinemia☆

Abstract: A 29-year-old man is described who has reduced concentrations of low density lipoprotein (LDL)-cholesterol seemingly due to an unusual variant of hypobetalipoproteinemia. The patient developed retinitis pigmentosa at age 14. When studied at age 28, his total cholesterol was 104 mg/dL, triglycerides 58 mg/dL, LDL-cholesterol 44 mg/dL, and HDL-cholesterol 51 mg/dL. Lipid and lipoprotein levels of his parents and sister were normal. His excretion of bile acids (13.9 mg/kg/d) was markedly elevated at about three times normal, although absorption rates of cholesterol and bile acids appeared to be in the normal range. His high excretion of bile acids equates to a threefold increase in bile acid synthesis. Isotope kinetic studies of his lipoproteins produced unexpected findings. Total production of VLDL-apolipoprotein B (apo B) was estimated to be 20.8 mg/kg/d, which was in the normal range. Synthesis of VLDL-triglycerides was also normal at 12.0 mg/kg/h. However, 75% of VLDL-apo B was removed directly from the circulation, which was much higher than values for direct removal of VLDL-apo B in control subjects. His production rate of LDL-protein (5.2 mg/kg/d) consequently was below normal, although his fractional catabolic rate for LDL (0.40 pools/d) was not distinctly elevated. These data suggest that the patient's hypobetalipoproteinemia was due to increased direct removal of VLDL remnants and not to reduced synthesis of VLDL-apo B; this abnormality may have been the result of enhanced activity of LDL receptors, which in turn was secondary to increased synthesis of bile acids.

Dietary therapy for different forms of hyperlipoproteinemia

Abstract: Diet is the first line of therapy for hypercholesterolemia. The major dietary factors raising the plasma cholesterol are saturated fatty acids, cholesterol, and excess total calories. For almost all forms of hyperlipidemia, the first principle of dietary therapy is to reduce saturated fatty acids, decrease cholesterol, and curtail excess calories. In patients with severe hypercholesterolemia, marked restrictions of diet may be necessary. For these patients, drugs may be required to control cholesterol levels. However, the majority of patients with elevated plasma cholesterol can achieve a satisfactory reduction of cholesterol levels by diet, and drugs will not be necessary. Dietary therapy alone is adequate for most patients with familial forms of hypertriglyceridemia, but for a few patients drugs are required.

Xanthogranulomatosis in an adult: Lipid analysis of xanthomas and plasma

Abstract: Xanthomatosis in the absence of hyperlipidemia is unusual but has been associated with compositional abnormalities of lipoprotein particles. An adult who developed juvenile xanthogranulomatosis in association with oral contraceptive ingestion is reported. Plasma lipids and lipoprotein electrophoresis were normal, as in a few other patients reported with this disorder. However, analysis of cutaneous xanthoma and plasma by thin-layer and gas-liquid chromatography revealed that cholesterol was the principal lipid in xanthoma and that there were no unusual sterols in plasma or tissue. Possible mechanisms of xanthoma formation are discussed. Thus juvenile xanthogranulomatosis should be considered in adults with normolipemic xanthomatosis. (J AM ACRD DERMATOL 1987;16:183-7.)

Diet and Coronary Heart Disease

Abstract: Diets low in total fats are widely recommended for the general public for the purpose of prevention of coronary heart disease (CHD). These diets lower the plasma cholesterol and low-density lipoproteins, and they are consumed in many countries where the prevalence of CHD is low. However, low-fat diets have not been widely accepted in the United States and other countries where rates of CHD are high. Although there has been a moderate reduction in fat intake among Americans, this change has not been sufficient to produce a major reduction in plasma cholesterol. For this reason, an alternate approach to lowering the plasma cholesterol by diet is needed.

The role of the LDL receptor in lipoprotein metabolism.

Abstract: The discovery of the LDL receptor in cultured mammalian cells by Goldstein and Brown in 1973 was followed by a rapid increase in our understanding of cellular and total body cholesterol metabolism1. The LDL receptor is the starting point for an intracellular pathway which is of fundamental importance in regulating cellular cholesterol metabolism. Studies in patients with Familial Hypercholesterolemia (FH), a genetic disease characterized by hypercholesterolemia and a partial or complete absence of LDL receptor activity, have shown that the LDL receptor is largely responsible for regulating the plasma LDL cholesterol concentration. It is also known that LDL receptor activity can be manipulated in vivo with dietary changes or medication to alter the plasma LDL cholesterol level for therapeutic purposes. Finally, the knowledge gained from animal studies that the liver contains large numbers of LDL receptors led to the use of liver transplantation to treat a young patient with the homozygous form of familial hypercholesterolemia. The results of that operation indicate that the human liver also contains a significant amount of LDL receptor activity. Since these findings are of major importance in developing ways to combat hypercholesterolemia-induced atherosclerosis, they will be reviewed in the following discussion.