Functional overlap between "chylomicra" and "very low density lipoproteins" of human plasma during alimentary lipaemia.
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Adult↗
Biomedical subjects
A Chait
Publications and source records attributed to A Chait.
Reduction of serum triglyceride levels by polyunsaturated fat. Studies on the mode of action and on very low density lipoprotein composition.
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Adult↗
Ascorbic acid clearance in diabetic nephropathy.
The incidence of cardiovascular disease is increased in diabetic nephropathy. Increased oxidative stress in diabetes is believed to play an important role in the pathogenesis of atherosclerosis in diabetes. Since antioxidant vitamins, such as ascorbic acid, often are reduced in diabetes, we hypothesized that the renal clearance of ascorbic acid is increased in patients with diabetic nephropathy. Thirty-seven subjects with diabetic nephropathy were studies: 18 had microalbuminuria (30-300 mg/day albuminuria); the remainder had clinical nephropathy (> 300 mg/day albuminuria). Indices of glycemic control (glucose, hemoglobin A1C) and renal function (albuminuria and creatinine clearance) were measured in addition to serum and urinary ascorbic acid levels. Results showed that subjects with clinical nephropathy had lower mean plasma ascorbic acid (p=0.0009) and higher renal clearance of ascorbic acid (p=0.005) than those with microalbuminuria. Bivariate analysis revealed an inverse correlation between creatinine clearance and AA clearance (r=-0.42, p=0.009). There was a significant linear association between the quantity of albuminuria and ascorbic acid clearance (r=0.49, p=0.002). Thus, patients with diabetic nephropathy have reduced ascorbic acid levels due to increased ascorbic acid clearance. The decrease in antioxidant defense that arises from the low levels of vitamin C may contribute to the increased cardiovascular morbidity and mortality observed in this population.
Adult↗
Probucol treatment affects the cellular composition but not anti-oxidized low density lipoprotein immunoreactivity of plaques from Watanabe heritable hyperlipidemic rabbits.
Use of the antioxidant probucol has been associated with a reduction in the development of atherosclerotic lesions in Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of familial hypercholesterolemia. In this study, atheromatous lesions from control or probucol-treated WHHL rabbits were probed with monoclonal antibodies to evaluate whether use of this drug either affected the presence or distribution of epitopes recognized by an antibody against oxidized low density lipoprotein or altered the cellular makeup of lesions. Although probucol-treated animals had much less aortic atherosclerosis than did controls, equivalent immunoreactivity for the anti-oxidized LDL antibody (OXL 41.1) was demonstrated in atherosclerotic lesions of both groups of animals, consistent with a role for oxidative modification of lipoproteins in atherogenesis in this animal model. Use of smooth muscle cell-specific (HHF-35) and macrophage-specific (RAM-11) antibodies demonstrated that lesions from probucol-treated animals were significantly smaller (p less than 0.01) and less cellular (p less than 0.05) than were control lesions. In addition, smooth muscle cells were the predominant cell type in lesions from probucol-treated animals, whereas macrophages predominated in lesions from controls (p less than 0.01). These findings are consistent with a reduction of monocyte/macrophage recruitment into or retention in lesions in probucol-treated animals, or with probucol-induced alterations in the production of growth factors or cytokines that might influence the cellular makeup of atherosclerotic lesions.
Animals↗
Phagocytosis of lipase-aggregated low density lipoprotein promotes macrophage foam cell formation. Sequential morphological and biochemical events.
Macrophages internalize aggregated low density lipoprotein (LDL) by LDL receptor-dependent phagocytosis. To investigate this model of foam cell formation, we have used human and mouse macrophages to characterize biochemically and morphologically the fate of ingested phospholipase C-modified low density lipoprotein (PLC-LDL). When LDL was digested with phospholipase C, it lost phospholipid and aggregated. Human monocyte-derived macrophages rapidly ingested and degraded 125I-PLC-LDL. The degraded PLC-LDL released free cholesterol, measured either as free sterol mass or by the stimulation of [14C]oleate incorporation into cellular cholesteryl ester. Esterification was blocked by chloroquine, a weak base that inhibits lysosomal degradation. Macrophages exposed to PLC-LDL exhibited a 30-fold to a 50-fold increase in esterified sterol: by light microscopy, cytoplasmic inclusions were abundant. The inclusions were stained with oil red O, indicating that they were neutral lipid droplets. By electron microscopy, mouse peritoneal macrophages incubated with PLC-LDL contained numerous membrane-bounded vacuoles and cytoplasmic inclusions that were not surrounded by a limiting membrane. Pulse-chase experiments demonstrated that vacuoles filled with particulate material appeared first. Subsequently, the macrophages exhibited vacuoles containing multivesicular bodies. Last, inclusions that were homogeneously electron-dense and that lacked a tripartite membrane accumulated in the cytoplasm of the cells. These results are consonant with the following model of foam cell formation. Cultured macrophages rapidly ingest PLC-LDL that is initially localized in phagosomes. The aggregated lipoprotein subsequently is digested in secondary lysosomes, thus releasing free cholesterol that is reesterified, forming cytoplasmic cholesteryl ester droplets lacking a tripartite membrane.
Foam Cells↗
A secretory product of human monocyte-derived macrophages stimulates low density lipoprotein receptor activity in arterial smooth muscle cells and skin fibroblasts.
The ability of macrophages to influence the metabolism of native low density lipoprotein by arterial smooth muscle cells was evaluated using cultured human monocyte-derived macrophages. Macrophage-conditioned medium stimulated the binding and degradation of low density lipoprotein by cultured arterial smooth muscle cells and skin fibroblasts. Sterol synthesis also was stimulated by macrophage-conditioned medium as was cholesterol esterification in the presence of high concentrations of low density lipoprotein. These findings suggest that macrophages secrete a factor that enhances the activity of the low density lipoprotein receptor. Low density lipoprotein degradation by arterial smooth muscle cells also was enhanced by macrophage-conditioned medium in the presence of high concentrations of low density lipoproteins in the medium. The macrophage factor that stimulates low density lipoprotein metabolism is stable to freezing, is inactivated by acid hydrolysis, tryptic digestion, and boiling, and is of large molecular weight (greater than 12,000 to 14,000 daltons). Modulation of arterial smooth muscle cell metabolism of low density lipoprotein by a macrophage secretory product may be of importance in the pathogenesis of atherosclerosis.
Binding Sites↗
Autoregulation of the modified low density lipoprotein receptor in human monocyte-derived macrophages.
Regulation of the macrophage receptor for modified low density lipoprotein (LDL) was evaluated using human monocyte-derived macrophages and acetyl LDL. Factors that regulate native LDL receptor activity in other cell types, such as the cholesterol content of the incubation medium, insulin, and platelet-derived growth factor had no effect on acetyl LDL degradation. Conditioned medium from mature macrophages significantly stimulated acetyl LDL degradation and enhanced cholesterol esterification by freshly isolated monocytes. Time course studies indicated that increasing time in culture was associated with increasing potency of the stimulating activity of macrophage-conditioned medium. These data suggest that a macrophage secretory product may be a prime modulator of modified LDL receptor activity on monocyte-macrophages, thus exerting an autocrine regulatory effect. The positive autoregulation of the human macrophage receptor for modified LDL could accelerate cellular cholesteryl ester accumulation and macrophage-derived foam cell formation.
Cell Differentiation↗
Fatty streak expansion and maturation in Watanabe Heritable Hyperlipemic and comparably hypercholesterolemic fat-fed rabbits.
This study focuses on the expansion and maturation of the fatty streak in the aorta of Watanabe Heritable Hyperlipemic rabbits and comparably hypercholesterolemic fat-fed rabbits between 2 and 6 months duration of hypercholesterolemia. In both groups of animals, the fatty streaks expanded due to: 1) the formation of multiple layers of a mixed population of macrophage-derived foam cells and lipid-containing smooth muscle cells, 2) the hypertrophy of the macrophage-derived foam cells, 3) the continued accumulation of extracellular matrix, 4) the insudation of plasma components. Immunocytochemical studies utilizing macrophage-specific and muscle-actin-specific monoclonal antibodies indicated that the expanding and mature fatty streaks in both the Watanabe and fat-fed rabbits were primarily composed of macrophage-derived foam cells. Hypertrophy of those foam cells situated immediately beneath the endothelium was associated with retraction of the endothelium and exposure of the intimal foam cells to the circulation. Endothelial retraction with exposure of intimal foam cells may facilitate entry of blood cells and lipoproteins into the lesions and formation of mural thrombi on the surfaces of the exposed cells. Biochemical analyses of the cholesterol content of the arteries indicated that both unesterified cholesterol and cholesteryl esters were deposited to a comparable degree in both the Watanabe and fat-fed rabbits. Thus, the absence of the low density lipoprotein receptor in Watanabe rabbits does not appear to directly influence the accumulation of cholesterol in the artery wall.
Animals↗
Superoxide initiates oxidation of low density lipoprotein by human monocytes.
Human mononuclear cells were used to evaluate the role of superoxide in the oxidation of low density lipoprotein (LDL). Unstimulated cells produced little superoxide or LDL oxidation as assayed by lipid peroxide content. Stimulation of the cells with phorbol myristate acetate (PMA) resulted in an increase both in superoxide production and in LDL oxidation. Mononuclear cell-mediated LDL oxidation was time- and cell number-dependent and was markedly enhanced by the presence of Fe (10 microM). Superoxide was required for the initiation of LDL oxidation as indicated by inhibition of the reaction by early addition of superoxide dismutase (SOD). Propagation of LDL oxidation was superoxide-independent, since the later addition of SOD resulted in progressively less inhibition of LDL oxidation. Propagation of LDL oxidation also was, in part, cell-independent as indicated by continued oxidation of LDL when mononuclear cells were removed following a 1 to 8 hour period with cells. Optimal LDL oxidation required the presence of mononuclear cells throughout the incubation period, suggesting that cellular factors in addition to superoxide play a role in LDL oxidation. Further evidence for the role of superoxide in the oxidation of LDL by mononuclear cells was obtained with cells from patients with genetic deficiencies of either superoxide generation (chronic granulomatous disease) or myeloperoxidase. PMA-stimulated cells from a patient with chronic granulomatous disease neither generated superoxide nor modified LDL. Incubation of LDL with cells from a patient with myeloperoxidase deficiency (in which superoxide production is normal or increased) resulted in oxidation of the lipoprotein equivalent to that observed with normal cells. Other inhibitors of oxidation reactions also were tested.(ABSTRACT TRUNCATED AT 250 WORDS)
Copper↗
Lipid composition of aorta of Watanabe heritable hyperlipemic and comparably hypercholesterolemic fat-fed rabbits. Plasma lipid composition determines aortic lipid composition of hypercholesterolemic rabbits.
Aortic and plasma lipid compositions were compared during a 12-month period in Watanabe heritable hyperlipemic (WHHL), comparably hypercholesterolemic fat-fed, and age-matched control normolipidemic rabbits to determine whether exposure to equivalent degrees of endogenous or exogenous hypercholesterolemia led to differences in the composition and concentration of lipids deposited in the artery wall. Although there were marked differences in the distribution of cholesterol among the lipoproteins in the WHHL versus the fat-fed rabbits, the contents of both free and esterified cholesterol were elevated to an equivalent degree in the aorta and plasma. In contrast, the triglyceride content of both the plasma and aorta were elevated only in the WHHL rabbits. However, aortic total phospholipids were increased in both the WHHL and fat-fed animals as compared to control rabbits. In the control rabbits, there was an age-dependent enrichment in aortic relative to plasma cholesteryl-oleate consistent with low density lipoprotein (LDL) receptor-directed intracellular cholesteryl ester processing. In contrast, enrichment in cholesteryl-oleate in aortae relative to plasma was not detected in either WHHL or fat-fed groups, suggesting that the plasma cholesteryl ester composition was the primary determinant of the aortic cholesterol composition. Thus, during chronic hypercholesterolemia, deposition of lipids in the artery wall appears to be determined by plasma lipoprotein levels and composition if the LDL receptor is either absent on a genetic basis or suppressed due to a high-fat, high-cholesterol diet.
Animals↗
Cholesterol accumulation in aortic smooth muscle cells exposed to low density lipoproteins. Contribution of free cholesterol transfer.
Incubation of cultured arterial smooth muscle cells with large concentrations of low density lipoproteins (LDL) resulted in a net increase in cell cholesterol and cholesteryl ester mass that was dependent on LDL concentration and time of incubation. Use of an inhibitor of acyl-CoA:cholesterol acyl-transferase (ACAT) reduced the accumulation of cholesteryl ester mass by 40% (range 25% to 50%), suggesting that a significant proportion of the cholesteryl ester mass that accumulated from LDL did so without being hydrolyzed and re-esterified. Quiescent arterial smooth muscle cells exposed for 48 hours to 0.5 mg/ml of 125I-LDL accumulated 115 nmol total sterol/mg cell protein. However, these cells took up and degraded only 21 micrograms of 125I-LDL protein, which contains 64 nmol total cholesterol. Hence, only about 60% of the increase in cell-associated cholesterol mass was accounted for by LDL particle uptake and degradation. Further, when cells were incubated with 3H cholesteryl linoleyl ether-labeled LDL, the net increase of total cell cholesterol was 81 nmol/mg cell protein. However, only 49 nmol of total cholesterol was taken up by LDL particle uptake, as calculated from the uptake of the 3H cholesteryl linoleyl ether tracer. It thus appears that about 40% of the accumulated cholesterol mass was derived independent of LDL particle uptake, suggesting the possibility of transfer of free cholesterol from the surface of LDL to the cell surface. The occurrence of cholesterol surface transfer was independently verified by the measurement of the uptake and cellular distribution of LDL-derived free 3H-cholesterol. A substantial fraction of the accumulated cell cholesterol mass (approximately 40%) was derived from surface transfer of LDL free cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Successful pregnancy outcome using total parenteral nutrition from the first trimester of pregnancy.
A 27-yr-old gravida 3, para 2 was supported from the 8th week of pregnancy by intermittent daily total parenteral nutrition (TPN) following the loss of her small bowel. Nutrient intake was adjusted by monitoring nitrogen balance and the rate of increase in fetal cranial enlargement. Maternal calcium balance proved difficult to maintain, since massive urinary Ca+2 losses occurred during infusion of nutrients (576 +/- 2 mg/12 hr on TPN compared to 47 +/- 12 mg/12 hr off). This increase in urine Ca+2 was due to depressed Ca+2 reabsorption by the kidney (87.1 +/- .7 vs 98.1 +/- .3%) and increased filtered load (4623 +/- 241 mg/12 hr vs 2591 +/- 329). Initially calcium balance was -180 mg/day. Nitrogen balance assessed by total stool and urine nitrogen was 1.1 g/24 hr, which was judged to be suboptimal. Deficits were corrected by increasing nitrogen intake, lengthening the duration of infusion and the oral administration of elemental calcium during periods off infusion. A normal fetus was delivered vaginally without complications at 351/2 weeks. This patient demonstrates that normal fetal growth and development as well as appropriate maternal weight gain and nitrogen balance can be maintained throughout pregnancy, including the first trimester, by intermittent daily TPN.
Adult↗
D-lactate and metabolic bone disease in patients receiving long-term parenteral nutrition.
D-lactate accumulates in some patients with malabsorption who continue oral intake of carbohydrate leading to a clinical syndrome of acidosis and encephalopathy. To assess the possibility that D-lactate contributes to acidosis and/or metabolic bone disease in patients with malabsorption receiving long-term parenteral nutrition yet maintaining oral intake, D-lactate levels in serum and urine were measured in 14 long-term parenteral nutrition subjects (average duration of support 74 months) and 27 control subjects. Significant elevations in both serum and urine D-lactate were found in only two parenteral nutrition subjects. Both subjects with elevated D-lactate levels had bone pain, x-ray evidence of fractures, and biopsy evidence of osteomalacia. These studies suggest that D-lactate accumulation may be a heretofore unappreciated metabolic abnormality associated with metabolic bone disease and acidosis in patients with malabsorption who are supported by long-term parenteral nutrition.
Acidosis, Lactic↗
Chylomicronemia syndrome in diabetes mellitus.
Lipemic plasma with marked elevations of plasma triglyceride levels (3221 +/- 1590 mg/dl) and fasting chylomicronemia was observed in nine patients with uncontrolled non-insulin-dependent diabetes mellitus. Every case had hypertriglyceridemic relatives, suggesting that the very high triglyceride values seen resulted from the coexistence of diabetes with a familial form of hypertriglyceridemia. A number of clinical and biochemical features observed in the diabetic patients and also in a group of nondiabetic controls with comparable degrees of hypertriglyceridemia suggests that these manifestations are related to high plasma triglyceride levels rather than to the diabetes per se. Chronic abdominal pain, mental confusion, and memory loss improved with lipid-lowering therapy and clearing the plasma of chylomicrons. Pulmonary function tests, red cell 2,3-diphosphoglycerate, and hemoglobin oxygen affinity were normal; the mild hypoxemia observed is believed to be an artifact. It is suggested that a syndrome due to chylomicronemia can occur in uncontrolled non-insulin-dependent diabetic patients, who in addition have a familial form of hypertriglyceridemia. To prevent manifestations of this syndrome in these patients, specific lipid-lowering therapy may be required in addition to control of their diabetes.
Abdomen↗
Calcitonin-induced impairment in conditioning is antagonized by chronic antidepressant drug treatment.
The purpose of this study was to test the effect of calcitonin, when injected into the lateral ventricle, on conditioning behaviour and to see whether antidepressant drug treatment can antagonize calcitonin-induced impairment of this behaviour. Conditioned response by conditional stimulus (CS) was compared in control rat (CO) and in rats that received intraventricular perfusion of calcitonin (CA), acute antidepressant drug treatment (ADa), acute antidepressant drug treatment + calcitonin (ADa + CA), chronic antidepressant drug treatment (21 days) + calcitonin the day after (ADc + CA). Control rats acquired easily the conditioned response, the CA group and ADa + CA had problems in making the correlation between CS and unconditional stimulus (US), and consequently did not acquire a conditioned response, but in the ADc + CA group, rats exhibited more conditioned responses. The results indicate that calcitonin disrupts conditioning processes and chronic but not acute antidepressant drug treatment can reverse the effects of calcitonin.
Analgesics↗
Dietary management of diabetes mellitus.
Since dietary regimes in diabetics need to be practiced lifelong, every effort should be made to facilitate acceptance of the recommendations made and, hence, compliance. A flexible approach that takes into consideration the patient's lifestyle, socioeconomic and ethnic factors, food preferences and personality has a much greater chance of success than the dogmatic and rigid approaches that have been practiced in the past. Finally, time spent on patient education is likely to reap rewards. The well-informed diabetic patient is the most important member of the team necessary for successful long-term management of diabetes.
Alcoholic Beverages↗