More on cholesterol.
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Anticholesteremic Agents↗
Biomedical subjects
N Kalant
Publications and source records attributed to N Kalant.
Inhibition by serum components of oxidation and collagen-binding of low-density lipoprotein.
Low-density lipoprotein (LDL) is oxidized by cellular and noncellular mechanisms, both leading to an increased binding to collagen. We have investigated the effect of serum on lipid peroxidation, apoprotein oxidation and the binding of oxidized apoprotein to collagen. During noncellular oxidation, lipoprotein-deficient serum strongly inhibited all three processes. The serum fraction of M(r) > 100,000 was equally inhibitory; this effect was not due to alpha 1 or gamma globulins, alpha 2 macroglobulins, haptoglobins or ceruloplasmin. The serum fraction of M(r) 30,000-100,000 stimulated the binding of oxidized apoprotein but the albumin in this fraction inhibited lipid peroxidation and apoprotein oxidation. Serum ultrafiltrate (M(r) < 1000) inhibited lipid and protein oxidation, and binding; the inhibitory effect was abolished by deionization which removed histidine. The effects of lipoprotein-deficient serum and its fractions on cellular oxidation were similar but weaker than those on noncellular oxidation, HDL inhibited noncellular oxidation as well as binding of oxidized apoprotein. VLDL also inhibited oxidation; this could not be accounted for by its content of apo B. If present in vivo, these inhibitory effects would completely suppress both cellular and noncellular oxidation of LDL and its subsequent binding to collagen.
Apolipoproteins B↗
Ionic versus nonionic contrast media: a burden or a bargain?
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Contrast Media↗
Angiogenic activity of the atherosclerotic carotid artery plaque.
Neovascularization is observed in complicated atherosclerotic plaques associated with cellular proliferation, plaque hemorrhage, and thrombosis. The angiogenic activity of 278 plaque fragments was tested; the fragments were taken from 12 patients with cerebral ischemia who underwent carotid endarterectomy. Angiogenesis, determined by the sustained ingrowth of new vessels in the rabbit cornea, was induced in 125 (45%) of these fragments. By contrast, angiogenesis was found in only two (2.4%) of 80 control tissues (p less than 0.001): in none of 22 samples of boiled atherosclerotic plaque; in two of 26 samples of normal rabbit carotid artery; and in none of 32 samples of nonatherosclerotic human uterine artery. Histological evaluation revealed that the cellular zones (composed mainly of smooth-muscle cells) were highly angiogenic, with 97 (76%) of 127 samples showing angiogenesis compared with 23 (17%) of 132 acellular fragments that consisted of amorphic, necrotic, calcific, lipid-laden material (p less than 0.001). These results indicate that angiogenesis in vivo is a function of the cellular component of the advanced atherosclerotic plaque, and is not expressed in the normal, stable arterial wall. The fragile new vessels could promote the growth of the plaque or be a source of hemorrhages, microinfarcts, and plaque fissures that convert a stable, silent lesion to an expanding, ulcerated, thrombotic, symptomatic plaque.
Aged↗
Recommendations from the Canadian Hypertension Society Consensus Conference on Hypertension and Diabetes.
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Canada↗
Compartmentation of glucose 6-phosphate in hepatocytes.
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Animals↗
Enhancement of glycogen concentrations in primary cultures of rat hepatocytes exposed to glucose and fructose.
Glycogen synthesis in isolated hepatocytes can occur from glucose both by a direct mechanism and by an indirect process in which glucose is first metabolized to C3 intermediates before use for glycogenesis via gluconeogenesis. We studied the incorporation into glycogen of glucose and the gluconeogenic substrate, fructose, in primary cultures of hepatocytes from fasted rats. In the presence of insulin, both glucose and fructose promoted net deposition of glycogen; however, fructose carbon was incorporated into glycogen to a greater extent than that from glucose. When glucose and fructose were administered simultaneously, the glycogenic utilization of glucose was stimulated 2-3-fold, and that of fructose was increased by about 50%. At constant hexose concentrations, the total incorporation of carbon, and the total accumulation of glycogen mass, from glucose and fructose when present together exceeded that from either substrate alone. Fructose did not change the relative proportion of glucose carbon incorporated into glycogen via the indirect (gluconeogenic) mechanism. The synergism of glucose and fructose in glycogen synthesis in isolated rat hepatocytes in primary culture appears to result from a decrease in the rate of degradation of newly deposited glycogen, owing to (i) decreased amount of phosphorylase a mediated by glucose and (ii) noncovalent inhibition of residual phosphorylase activity by some intermediate arising from the metabolism of fructose, presumably fructose 1-phosphate.
Animals↗
Effect of diet restriction on glucose metabolism and insulin responsiveness in aging rats.
The effect of age and of prolonged caloric restriction on glucose tolerance and insulin responsiveness has been studied in male Fischer 344 rats. Beginning at 1 month of age dietary intake of an experimental group (R) was limited to 60% of that of the control group (AL) which was allowed to eat ad libitum. Studies were carried out at intervals up to 24 months of age. In AL rats the oral glucose tolerance curve showed progressively higher peak levels of plasma glucose with age, and a decrease in the plasma insulin concentration at the time of the glucose peak. The R group did not show the increase in peak value with age and the corresponding insulin concentration was lower than that of the AL group. These results are compatible with a delay in the first phase of insulin secretion in aging AL rats. Insulin-stimulated glucose disposal was assessed by the method of Reaven et al. [Diabetes, 32 (1983) 175], at ages 4, 12, 18 and 24 months; using infusions of 2 mU of insulin and 1 mg of glucose/min per kg, the steady-state plasma glucose level (SSPG) was slightly lower in R than in AL rats, while the steady-state plasma insulin level was reduced by 40-60%. In rats aged 18-24 months the hepatic glucose output, measured with [3-3H]glucose, was the same for AL and R rats in the basal state and was reduced to the same extent by insulin. In the presence of epinephrine and propranolol, infusion of glucose and insulin at various rates demonstrated that the plasma glucose clearance rate increased linearly with increasing SSPI, and at comparable SSPI levels was lower in R than in AL rats. The ability of insulin to stimulate glycogenesis from glucose was measured in primary hepatocyte cultures. Insulin increased glycogenesis 3-fold in cells from AL rats and 4-6-fold in cells from R rats. There was no effect of age. The increased insulin responsiveness of R rats was not due to an increase in insulin binding or to a decrease in insulin degradation (measured with intact cells or as cytosolic insulinase activity).(ABSTRACT TRUNCATED AT 400 WORDS)
Aging↗
Influence of collagen gel substratum on response to low-density lipoprotein by cultured human skin fibroblasts.
The effect of low-density lipoprotein (LDL) on accumulation of glycosaminoglycans (GAG) was compared in cultures of human skin fibroblasts on a conventional plastic substratum and in a native type I collagen gel. The 24-h incorporation of [3H]glucosamine and Na2(35)SO4 into GAG secreted into the medium or associated with the substratum and cell surface (SCA) was measured in cells at subconfluent densities. When cells were grown on plastic, 13-25% of the labeled GAG was in the SCA pool. Cells cultured within a collagen gel matrix incorporated three times more [3H]glucosamine and up to five times more [35S]sulfate into this pool. The addition of LDL (300 micrograms protein/mL) to the medium increased the level of total GAG incorporation of [3H]glucosamine by 40-50% and of [35S]sulfate by 15-20% on both substrata. For cells on plastic the relative increase in the medium and SCA pool was similar, whereas for cells in collagen gel the response to LDL was twice as great in the SCA pool as in the medium. The distribution of GAG types was unaffected by LDL; hyaluronic acid remained the principal GAG in the media pools of both substrata, heparan sulfate remained the main SCA GAG in cultures on plastic, and dermatan sulfate remained the dominant GAG in the SCA pool of collagen gel cultures. LDL degradation was measured at intervals up to 48 h after the addition of 125I-labeled LDL. The rate of accumulation of degraded LDL products was lower in collagen gel cultures, but the final levels achieved were the same in the two substrata. Concentrations of total cell cholesterol were similar, although the increases in free cholesterol induced by LDL were 26% greater in cells within collagen gel than in those on plastic. We conclude that fibroblasts grown within a collagen gel, as compared with those on a plastic substratum, (i) accumulate more GAG that remain attached to the substratum and cell surface; (ii) respond to LDL with a similar degree of increase in GAG accumulation, but more of the increase is found in the substratum and cell surface compartment; and (iii) accumulate more intracellular free cholesterol in response to LDL.
Cells, Cultured↗
Time-dependent alterations in the pathway of glucose incorporation into glycogen in primary cultures of rat hepatocytes following glucose starvation.
Isolated rat hepatocytes maintained in primary culture were able to use glucose for glycogen synthesis by both direct and indirect mechanisms. Cells that had been isolated from fed animals and then cultured in the absence of glucose, but in the presence of gluconeogenic substrates such as pyruvate and amino acids, had decreased glycogen contents compared with similar cells that had been cultured in the presence of glucose. Upon reexposure to glucose, the glucose-starved cells showed time-dependent changes in the preferred pathway for the use of glucose for glycogen synthesis. These changes were noted either in the absence or presence of insulin; however, net accumulation of glycogen was observed only in the presence of the hormone.
Animals↗
The effects of acute and life-long food restriction on basal and stress-induced serum corticosterone levels in young and aged rats.
The effects of short term (1-month) and life-long 60% ad libitum food restriction on the adrenocortical response to restraint stress were compared in young and aged Fischer 344 rats. In rats restricted for 1 month (study 1), the adrenocortical response differed as a function of age. In 8-month-old animals, the initial steep rise in corticosterone in response to stress was of similar magnitude in ad libitum and restricted animals. In 23-month-old animals the corticosterone response was severely blunted in restricted animals. In life-long restricted animals (study 2), the corticosterone response to restraint stress was tested at 8, 16, and 24 months of age. The general pattern of response to stress in these animals was similar to that in study 1. The 16- and 24-month-old animals showed the same blunted response to stress found in the 23-month-old animals restricted for only 1 month, suggesting that the severe restriction per se and not life-long food restriction blunted the response to stress in aged animals. The similarity between the response to stress in study 1 and study 2 was evident even though animals were tested in one case before feeding when corticosterone levels were high, and in the other 4-5 h after feeding when corticosterone levels were lower. In study 3 it was found that in food-restricted young rats, the mean corticosterone level over a 24-h period was significantly elevated above that in ad libitum fed young rats. In aged rats, however, except before daily feeding, corticosterone levels of food-restricted rats remained significantly below those of ad libitum fed animals, whose levels were, in turn, significantly elevated compared to those of ad libitum fed young rats. These findings suggest that in aged animals severe food restriction reduces basal corticosterone levels, adrenal responsiveness to stress, and adrenal size and has the potential to protect against the consequences of high corticosterone levels in aging.
Adrenal Cortex↗
Compartmentation of glucose 6-phosphate in hepatocytes.
Rat hepatocytes were incubated with 14C-labelled hexoses, and the specific radioactivities of glucose 6-phosphate, glucose 1-phosphate and fructose 6-phosphate were determined. (1) When suspensions of freshly isolated hepatocytes were incubated with [14C]glucose, the specific radioactivities of glucose 1-phosphate and fructose 6-phosphate were severalfold higher than that of glucose 6-phosphate. The ratios of the specific radioactivities decreased with time of incubation. These relationships were also found when incubations were carried out with primary cultures of rat hepatocytes or with crude homogenates of hepatocytes, but not with isolated nuclei. (2) When cells were incubated with [14C]fructose, the ratios of the specific radioactivities were higher than with [14C]glucose, and also decreased with time. (3) Paired incubations were carried out with a mixture of galactose and fructose, with one or other sugar being labelled with 14C. The specific radioactivity of glucose released into the medium was greater than that of glucose 6-phosphate when fructose was labelled, but not when galactose was labelled. Furthermore, glucose 6-phosphate and glucose in the medium differed with regard to the distribution of 14C between C-1 and C-6. These results are interpreted as evidence that glucose 6-phosphate in hepatocytes does not exist as a homogeneous pool, but that subcompartments exist which are associated with glucose phosphorylation, gluconeogenesis and glycogenolysis.
Animals↗
Hepatic glucose extraction in normal and diabetic man.
Fractional hepatic extraction of glucose was determined from the appearance in the systemic circulation of ingested 3-[3H]glucose. Using the glucose clamp technique, studies were done under steady-state conditions of basal glycemia and insulinemia, normoglycemia (0.8 mg/mL) and mild hyperinsulinemia (approximately 40 microU/mL), hyperglycemia (2 mg/mL-1) and hyperinsulinemia (approximately 100 microU/mL). Based on previous results in the dog, an oral glucose load of 2 g was used to label the portal vein glucose; this amount was chosen so as to minimize disturbance of the portal steady state but still avoid excessive loss during absorption. Additional subjects with hyperglycemia and hyperinsulinemia received an oral load of 50 g of glucose. Fractional extraction in normal subjects under near-basal conditions of glycemia and insulinemia was 19% in normal subjects and in patients with noninsulin-dependent diabetes mellitus (NIDDM) elevation of serum insulin, with or without hyperglycemia, which led to an average extraction rate of 32% of the ingested glucose. Absolute hepatic glucose uptake, calculated from the fractional extraction the plasma glucose concentration, and hepatic plasma flow accounted for 50% to 72% of total glucose use during the various steady states and following ingestion of 50 g of glucose. It is concluded that hepatic uptake or extraction, as opposed to net uptake, proceeds actively even when plasma glucose and insulin are within the normal basal range; it is increased in the presence of hyperinsulinemia, with or without hyperglycemia; and it is unaltered in NIDDM.
Adult↗
First-pass hepatic uptake and utilization of glucose in the rat.
First-pass hepatic retention of glucose had previously been measured indirectly from the appearance of ingested labelled glucose into the systemic circulation. To determine the accuracy of the procedure, results obtained by this indirect method were compared with those of direct measurement of hepatic retention of labelled glucose given by instantaneous injection into the portal vein. In the rat, the indirect procedure gave a value of 13.7 +/- 2.3%. In the direct method, [14C]glucose was injected intraportally together with [3H]sucrose as a marker of extracellular distribution. Hepatic content of both labels was maximal immediately after administration; the content of sucrose fell to basal values by 15 s, indicating that the injected bolus had passed through the liver; the content of [14C]glucose continued to fall for 90 s. The difference in tissue retention between glucose and sucrose, representing intracellular glucose, was constant from 90 to 180 s, and indicated a first-pass retention of 13 +/- 0.7%. Thus the indirect procedure gives a reliable estimate of hepatic uptake and retention of glucose. Comparison of the time courses of hepatic content of [14C]glucose, [2-3H]glucose and [3H]sucrose indicated that 50% of portal-vein glucose enters the hepatic cells; subsequently 15% traverses the glucose/glucose 6-phosphate futile cycle, 22% is released without undergoing metabolic change and 13% is retained for metabolic purposes.
3-O-Methylglucose↗
Absorption of an oral glucose load in the dog.
Absorption of glucose from the gut was estimated in trained unanesthetized dogs given a glucose load of 1-25 g (14C)glucose by stomach tube. The rate of absorption of glucose was calculated from the concentration and specific activity of glucose in the portal vein and in an "arterialized" peripheral vein. When the rate was integrated over time it was found that 94 +/- 4% of the administered glucose was recovered from the portal vein as glucose; this was unrelated to the size of the glucose load. It is concluded that absorption does not entail a significant loss or conversion to glucose metabolites.
Animals↗
Incorporation of glucose into glycogen in primary cultures of rat hepatocytes.
Glucose may be incorporated into glycogen both by an indirect pathway that involves the metabolism of glucose to C3 intermediates prior to incorporation into glycogen and by a direct mechanisms that utilizes the sequence glucose----glucose-6-P----glucose-1-P----UDP-glucose----glycogen. Studies were carried out to determine the major pathway in primary cultures of rat hepatocytes. When cells were incubated with medium containing [3-3H]- and [14C(U)]-glucose the ratio of 3H/14C in glycogen was 70-80% of that of the glucose in the medium. This ratio was unaffected by increases in glucose concentration or insulin, both of which promoted large increases in the incorporation of glucose into glycogen. Relative 3H/14C ratios in glycogen of 25-30% were observed when [2-3H]- and [14C(U)]-glucose was employed; this ratio was doubled in the presence of 2-deoxyglucose or sorbitol, each of which inhibits phosphohexose isomerase. It is concluded that about 75% of the glucose undergoes isomerization between glucose-6-P and fructose-6-P, while about 25% is further glycolysed to C3 intermediates, prior to incorporation. Lactate added to the medium was incorporated into glycogen to an extent of only 20% of that of glucose. However, the presence of lactate resulted in a large increase in the incorporation of glucose into glycogen. Little net deposition of glycogen was observed in these studies. It is concluded that cultured hepatocytes may be a model for the fed organism, and in this condition the direct pathway for the incorporation of glucose into glycogen was predominant.
Animals↗
Regulation of insulin binding and stimulation of sugar transport in cultured human fibroblasts by sugar levels in the culture medium.
Studies were carried out on cultures of human skin fibroblasts to explore the effects of culture medium glucose levels on insulin binding and action. Cell cultures in 5.55 mM glucose-containing medium depleted their medium glucose within 3 days, and at that time exhibited elevated deoxy-D-glucose (2-DG) transport (84% greater than control cultures fed 22.2 mM glucose) and failure of insulin to stimulate 2-DG transport (an insulin:control transport ratio of 1.02). There was also a significant negative correlation between basal 2-DG transport and insulin binding (r = -0.621; n = 29; P less than 0.01), while insulin binding exhibited a significant positive correlation with insulin action (r = 0.816; n = 12; P less than 0.01). Glucose starvation of cultures for 18 h resulted in several changes: a 49% decrease in specific 125I-insulin binding due to a reduction in binding capacity; elevated basal 2-DG transport; and an absence of insulin stimulation of 2-DG transport. Exposure to increasing concentrations of glucose for 18 h led to a glucose concentration-dependent increase in specific insulin binding. Additionally, the various changes in the glucose-starved group were reversed after as little as 6 h of glucose refeeding. The results indicate that basal sugar transport, and insulin binding and action can be regulated by the amount of glucose in the medium.
Biological Transport↗
Interaction of high and low density lipoproteins on glycosaminoglycan secretion by human vascular smooth muscle cells and fibroblasts.
Low density lipoprotein (LDL) increased secretion of glycosaminoglycans (GAG) and the cell cholesterol content of proliferating fibroblasts and smooth muscle cells in culture; with increasing cell density the GAG effect decreased, but the cholesterol effect did not. High density lipoprotein (HDL, d greater than 1.063) decreased GAG secretion by slowly proliferating cells; when cells were actively proliferating, HDL alone did not affect GAG secretion, but it inhibited the increase caused by LDL. Thus HDL appeared to influence GAG secretion by two separate mechanisms, an inhibition which was overcome by rapid proliferation and an anti-LDL effect. HDL2 (d = 1.063-1.100) partially reproduced the latter effect. In addition, HDL, HDL2, and HDL3 increased cell cholesterol; the ability of LDL to increase cholesterol was correspondingly reduced in the presence of HDL and its subfractions, suggesting that they act by common mechanisms.
Acetates↗