PubMed Health⌕ Search

Biomedical subjects

A D Sniderman

Publications and source records attributed to A D Sniderman.

At least 91 records · Page 5Linked to original sources
PubMed1992

Pathogenesis of carbohydrate-induced hypertriglyceridemia using HepG2 cells as a model system.

This study compares the effects of glucose and fatty acid on hepatic lipid synthesis and apolipoprotein (apo) B secretion. To do so, varying concentrations of either glucose or oleic acid were added to the medium in which HepG2 cells were being incubated. Intracellular triacylglycerol and cholesteryl ester synthesis and secretion were measured by addition of radioisotopic tracers and by determination of mass, whereas apo B concentration in the medium was measured by a specific enzyme-linked immunosorbent assay. The data indicate that increasing concentrations of glucose in the medium resulted in increased synthesis of triacylglycerol within the cell and increased secretion of triacylglycerol into the medium. Apo B secretion into the medium, however, did not change, and intracellular synthesis and secretion of cholesteryl ester did not change as well. By contrast, addition of oleic acid to the medium resulted in increased synthesis and secretion of both cholesteryl ester and triacylglycerol, and this was associated with increased secretion of apo B into the medium. Thus, a carbohydrate load resulted in secretion of normal numbers of triacylglycerol-enriched apo B particles by this hepatocyte cell line, whereas a fatty acid load led to the secretion of increased numbers of apo B particles, which were essentially normal in composition.

Apolipoproteins B↗
PubMed1992

The measurement of apolipoprotein B should replace the conventional lipid profile in screening for cardiovascular risk.

This was the timely topic debated by Dr Allan Sniderman (protagonist) and Dr Jacques Genest Jr (antagonist) at the ninth internation symposium on atherosclerosis, October 7, 1991, in Chicago-Rosemont, Illinois. Dr Maurice Mishkel, Professor Emeritus and founder of the McMaster Lipid Research Clinic moderated the event which was made possible by an educational grant from Sandoz Canada.

Apolipoproteins B↗
PubMed1992

The relation between triglyceride synthesis in peripheral tissues and postprandial plasma triglyceride levels: preliminary evidence of a role for acylation stimulating protein.

The present study examines the hypothesis that the rate at which peripheral tissues synthesize triglycerides is a key determinant of the rate at which they are removed from plasma. The cells of greatest interest in this regard would, of course, be the adipocytes. However, serial sampling of this tissue is not possible in man. We have approached the question indirectly, by studying triglyceride synthesis in human mononuclear cells before and after an oral fat load. In addition, plasma levels of Acylation Stimulating Protein (ASP) were measured after an overnight fast and 4 h after ingestion of the oral fat load. Similar measurements were made in the same subjects after fasting overnight and with the fast extended for 4 additional hours. With the extended fast, no parameter measured changed significantly. However, after the oral fat load, the following changes were found to be significant: plasma triglycerides increased (63.6 +/- 31.1 vs 101.5 +/- 43 mg/dl, p less than 0.005) as did d less than 1.006 g/ml triglycerides (42.3 +/- 22.8 vs 78.0 +/- 39.7 mg/dl, p less than 0.005) and plasma ASP (10.4 +/- 2.2 vs 14.7 +/- 2.3 mg/dl, p less than 0.005). In addition, the rate of triglyceride synthesis in the mononuclear cells increased significantly (1.22 +/- 0.3 vs 1.52 +/- 0.3 nmol oleate/mg cell protein per h, p less than 0.005). There was also a significant inverse relation between the increase in the d less than 1.006 triglycerides between 0 and 4 h and the increase in triglyceride synthesis in the mononuclear cells (r = 0.91, p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Acylation↗
PubMed1991

Effect of acylation stimulating protein on the triacylglycerol synthetic pathway of human adipose tissue.

Acylation stimulating protein (ASP) is a 14 kDa plasma protein which causes in vitro triacylglycerol synthesis in human adipocytes and fibroblasts to increase substantially. ASP was found to stimulate human adipose tissue microsomal glycerophosphate acyltransferase and diacylglycerol acyltransferase activities by 23% and 90%, respectively. However, phosphatidate phosphohydrolase activity showed no increase in activity, nor did microsomal acyl-CoA synthetase activity. Moreover, ASP did not decrease the apparent Km of diacylglycerol acyltransferase (DGAT), but rather increased its apparent Vmax suggesting direct interaction of ASP with DGAT.

Acyltransferases↗
PubMed1991

Levels of acylation stimulating protein in obese women before and after moderate weight loss.

Acylation stimulating protein (ASP) is a small (MW 14,000) basic (pI 9.0) protein which has only recently been purified from human plasma. Since ASP is the most potent known stimulant of triglyceride synthesis in human adipose tissue, the present study was designed to determine if plasma ASP was elevated in patients with moderate obesity, and if so, whether this level changed with weight loss. Fasting plasma ASP levels were determined by competitive ELISA immunoassay in 10 obese women before weight loss, immediately after weight loss, and 3 months after maintaining weight reduction. Their plasma ASP results were compared to 17 age and sex-matched lean controls. With weight loss, plasma ASP decreased significantly: 19.6 +/- 10.7 mg/dl before weight loss vs 15.0 +/- 9.5 mg/dl after weight loss vs 13.8 +/- 7.7 mg/dl 3 months after being weight stable, P less than 0.05 initial vs final value. Nevertheless, plasma ASP was significantly higher than the control value at all three times. Thus, before weight loss, the average ASP in the obese group was four times that in the control group (19.6 +/- 10.7 vs 5.1 +/- 3.6 mg/dl, P less than 0.0005) while even 3 months after weight loss, it remained almost three times above the control group (13.8 +/- 7.7 vs 5.1 +/- 3.6 mg/dl, P less than 0.0005). The data suggest, therefore, that an elevated plasma level of ASP is common in obesity, that the level of plasma ASP may reflect the fat cell mass present in an individual, and raises the possibilities that ASP may play a role in initiation or maintenance of the obese state.

Adult↗
PubMed1990

Modulation of chylomicron remnant metabolism by an hepatic hydroxymethylglutaryl coenzyme A reductase inhibitor.

This study was designed to test the hypothesis that in patients with elevated plasma low-density lipoprotein (LDL) apolipoprotein-apoB, chylomicron remnant clearance can be modulated by therapy with a hepatic hydroxymethyl glutaryl coenzyme A reductase inhibitor. Accordingly, chylomicron triglyceride and remnant clearance were determined following a vitamin-A fat load in 12 such patients, before and after therapy with Lovastatin (Merck, Sharp & Dohme, Rahway, NJ). Such therapy had no significant overall effect on plasma triglyceride clearance, although there was a trend to lower levels of Sf greater than 400 triglycerides at the later time points. By contrast, retinol clearance in plasma and Sf greater than 400 lipoproteins was markedly increased (30% and 40%, respectively). The data indicate, therefore, that following therapy with Lovastatin in this group of patients, chylomicron plasma remnant clearance was significantly enhanced. The exact mechanisms responsible remain to be explicated.

Apolipoproteins B↗
PubMed1990

Impaired response of fibroblasts from patients with hyperapobetalipoproteinemia to acylation-stimulating protein.

Acylation-stimulating protein (ASP) is a small, basic, human plasma protein that markedly stimulates triglyceride synthesis in human adipocytes and cultured human skin fibroblasts. The present studies examine the response to ASP of cultured skin fibroblasts from normal subjects patients with hyperapobetalipoproteinemia, patients with familial hypercholesterolemia, and patients with hypertriglyceridemia without hyperapobetalipoproteinemia. Triglyceride synthesis induced by ASP did not differ significantly among the normals, the patients with familial hypercholesterolemia, and the patients with hypertriglyceridemia with normal low density lipoprotein (LDL) apolipoprotein B levels; however, on average, it was markedly reduced in the patients with hyperapobetalipoproteinemia. In all groups studied, evidence of specific saturable binding of radioiodinated ASP was present. Binding, however, was significantly reduced in the groups with hyperapobetalipoproteinemia whereas the other three groups were indistinguishable. By contrast, LDL-specific binding was reduced only in the patients with familial hypercholesterolemia. There was a significant direct relation between the degree of ASP binding and the triglyceride synthesis inducible by ASP. In addition, with the exception of the patients with familial hypercholesterolemia, there was an inverse relation between both ASP-specific binding and ASP-induced triglyceride synthesis in fibroblasts to LDL levels in plasma whereas no relation was evident to plasma high density lipoprotein and very low density lipoprotein.

Adolescent↗
PubMed1990

Regulation of apoB secretion from HepG2 cells: evidence for a critical role for cholesteryl ester synthesis in the response to a fatty acid challenge.

Secretion of hepatic apoB lipoproteins removes excess triglyceride from the liver. However, the mechanism by which synthesis of apoB, which occurs on the rough endoplasmic reticulum, is coordinated with synthesis of triglyceride, which takes place in the smooth endoplasmic reticulum, is not known. To examine this question, we have manipulated intracellular synthesis of triglyceride and cholesteryl ester in HepG2 cells and determined the impact of these maneuvers on apoB secretion. Since cholesteryl ester is the only major lipid class synthesized in the rough endoplasmic reticulum, our hypothesis was that, in response to a fatty acid challenge, synthesis of cholesteryl ester rather than synthesis of triglyceride would be the immediate trigger to apoB secretion. Oleate complexed to bovine serum albumin caused intracellular triglyceride synthesis to increase 6-fold and cholesteryl ester synthesis to increase almost 3-fold, while apoB secretion into the medium increased by 2.5-fold (P less than 0.0125) at all time points between 4 and 24 h. Addition of acylation stimulating protein to the medium further stimulated both triglyceride and cholesteryl ester synthesis (58% and 108%, respectively) above oleate alone and this resulted in a 50% increase in apoB secretion (P less than 0.0025). By contrast, both progesterone and 2-bromooctanoate inhibited triglyceride and cholesteryl ester synthesis and these effects were associated with reduced apoB secretion. Lovastatin inhibited cholesteryl ester synthesis (45%, P less than 0.0025); however, at the doses used, triglyceride formation was unaffected. Under these circumstances, apoB secretion was reduced by 25% (P less than 0.05). Similarly, 58-035 (an inhibitor of acyl CoA:cholesterol acyltransferase) on the one hand reduced cholesteryl ester synthesis markedly (59%, P less than 0.005), but on the other increased triglyceride synthesis though not statistically significantly (65%, P NS), and again this resulted in decreased apoB secretion (25%, P less than 0.005). Control experiments established that changes in low density lipoprotein catabolism did not contribute importantly to the quantity of apoB in the medium. Taken together, the data indicate that, at least in HepG2 cells, there are parallel changes in cholesteryl ester synthesis and apoB secretion and suggest that it is cholesteryl ester synthesis, not triglyceride synthesis, that is the immediate regulator of apoB secretion when these cells are exposed to an increased influx of fatty acids. However, alternative or additional regulatory mechanisms, such as, for example, a role for acylation of apoB, are not excluded by these studies.

Apolipoproteins B↗
PubMed1990

Inspiratory reduction in left heart filling as a mechanism of pulsus paradoxus in cardiac tamponade.

Pulsus paradoxus occurs in cardiac tamponade because the output of the left ventricle falls during inspiration. The principal cause for this is reduced filling of the left ventricle during the preceding diastole. The present study examines whether this reduced filling of the left ventricle on inspiration is due to compression by the right heart or due to reduced venous return to the left heart. The effect of pericardial tamponade on hemodynamics and left ventricular and atrial volumes was determined in six experimental animals. The data demonstrate that from the outset pericardial fluid reduces left ventricular end diastolic volume, although initially left ventricular end systolic volume decreases as well. By contrast, pulsus paradoxus is a relatively late phenomenon occurring with severe tamponade and associated with an inspiratory decrease in left atrial and ventricular volumes in the face of a drop in left ventricular filling pressure. Underfilling of the left heart is the most likely cause of this combination of events.

Animals↗
PubMed1989

Role of anemia in the pathogenesis of left ventricular hypertrophy in end-stage renal disease.

Left ventricular (LV) hypertrophy is common in end-stage renal disease, yet the factors associated with its development are poorly understood. LV mass index was determined by echocardiography in 78 patients who had been treated by dialysis for at least 3 months. A significant relation was evident between anemia and LV hypertrophy. The mean LV mass index was 158 +/- 6 g/m2 (mean +/- standard error) in patients in the lowest quartile of serum hemoglobin and 140 +/- 10, 132 +/- 7 and 120 +/- 8 g/m2 in the second, third and uppermost quartiles, respectively (p = 0.005). This relation persisted after adjusting for systolic blood pressure, treatment mode and suspected coronary artery disease. Forty-eight patients had paired studies. In these, LV mass index increased as hemoglobin decreased (coefficient = -0.81 g/m2/g/liter, p less than 0.025). These data indicate that anemia contributes to the development of LV hypertrophy in patients with end-stage renal disease.

Adult↗
PubMed1989

Purification and characterization of acylation stimulating protein.

We have purified to homogeneity and analyzed the amino acid composition of a small (Mr 14,000), basic (pI 9.0) protein from human plasma. This has been named acylation stimulating protein (ASP) because it markedly stimulates triacylglycerol synthesis in human adipocytes. As well, it stimulates triacylglycerol synthesis in human skin fibroblasts cultured from normal individuals. Characteristic saturation curves for the cell metabolic responses to ASP were observed in both cell types with higher stimulation of oleate incorporation into triacylglycerol being observed in adipocytes. The stimulation of triacylglycerol synthesis was much greater with ASP than with insulin. Neither fatty acid binding protein nor albumin was able to mimic the ASP effect.

Adipose Tissue↗
PubMed1989

A demonstration of vascular proliferation in response to arteriovenous reversal in the ischemic canine hind limb.

Patients with diffuse peripheral vascular disease, resulting in inadequate arteriographic runoff, and/or multiple failed bypasses almost inevitably face amputation. We have previously used an arteriovenous reversal (AVR) procedure at the popliteal level to salvage severely ischemic canine hind limbs. This procedure is followed by the development of an intense network of new vessels in the proximity of the arteriovenous anastomosis. The present study was designed to define the nature of these vessels and their role in providing nutrient perfusion to the limb. Using an established model to create severe limb ischemia. AVR was performed in 24 dogs. Tissue perfusion and neovascularization were assessed by angiography, transcutaneous oximetry (TcpO2), tritiated thymidine uptake combined with autoradiography, and histologic capillary density measurements. Angiography revealed the intense vascular network in the region of the anastomosis by postoperative Day 22 in all dogs. TcpO2 on Day 1 was indicative of severe ischemia in the operated calf compared to controls (12 vs 80 mm Hg, P less than 0.01) but returned to normal by Day 22 (81 vs 76 mm Hg). A progressive, significant increase in tritiated thymidine uptake was seen by Day 22 (0.36 vs 0.27 microCi/g, P = 0.005); on autoradiography 95% of these labeled nuclei in the operated limbs were in endothelial cells compared to only 5% in the control limbs. Finally, capillary density studies of the calf muscles showed a substantial increase in the operated limbs (mean, 1011 vs 605 cap/mm2, P = 0.0004). These studies suggest that the dramatic increase in vascularity observed angiographically following AVR in a severely ischemic limb consists primarily of a rapidly expanding capillary network.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The effect of ASP on the adipocyte of the morbidly obese.

The control of triglyceride synthesis within the adipocyte is not fully understood. Insulin is considered to be the most potent stimulant of triglyceride synthesis. In this paper, we report on the effect of a small (14000 Da), basic (pI 9.0) protein isolated from human serum. This protein has been called acylation stimulating protein (ASP). It is a potent stimulant of triglyceride synthesis in adipocytes from both normal weight and morbidly obese subjects. Its stimulatory effect on adipocytes is both rapid, occurring between 15-30 min after the start of incubation, and prolonged, lasting for up to 3 hr. Compared to insulin, it is sixfold more potent in its effect on triglyceride synthesis. As well as acting on isolated cells, ASP also has a fourfold stimulatory effect on triglyceride synthesis in human adipose microsomes at a concentration of 25 micrograms/ml. This study indicates that ASP is a potent stimulant of triglyceride synthesis and therefore may play a role in the pathogenesis of morbid obesity.

Adipose Tissue↗
PubMed1989

Impact of left ventricular hypertrophy on survival in end-stage renal disease.

We examined the prognostic significance of left ventricular hypertrophy determined by echocardiography in a cohort beginning renal replacement therapy. No patient had hemodynamically significant valvular disease or echocardiographic signs of obstructive cardiomyopathy. Using the Cox proportional hazards model, left ventricular hypertrophy was significantly associated with survival. The relative risk, based on comparison of upper and lower quintiles of left ventricular mass index, was 3.7 (95% confidence intervals, 1.6 to 8.3) for all-cause mortality and 3.7 (95% confidence intervals, 1.2 to 11.1) for cardiac mortality. The independent risk, adjusted for age, known coronary artery disease, diabetes, level of systolic blood pressure, and treatment (dialysis or transplantation), was 2.9 (95% confidence intervals, 1.3 to 6.9) for all-cause mortality and 2.7 (95% confidence intervals, 0.9 to 8.2) for cardiac mortality. Therefore, left ventricular hypertrophy appears to be an important, independent, determinant of survival in patients receiving therapy for end-stage renal failure.

Cardiomegaly↗