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Biomedical subjects

C J Fielding

Publications and source records attributed to C J Fielding.

At least 73 records · Page 4Linked to original sources
PubMed1986

Abnormal plasma cholesterol metabolism in cigarette smokers.

Plasma cholesterol metabolism was studied in young, nonobese, normolipidemic men with a moderate level of cigarette smoking (24 +/- 5d-1) and in a comparable nonsmoking normal control group. The smokers showed a decreased cholesterol net transport from cell membranes into plasma (P less than 0.001) and a decreased ratio of cholesteryl ester transfer to low and very low density lipoprotein, relative to lecithin:cholesterol acyltransferase (P less than 0.05). Apoprotein E was increased in smokers' plasma (P less than 0.05) whereas apoprotein A-I, the major apoprotein of HDL, was decreased (P less than 0.05). This pattern of abnormalities has been previously observed in several other groups of subjects at increased risk for atherosclerotic vascular disease (diabetics, dysbetalipoproteinemics, and hyperbetalipoproteinemics). These data suggest a deleterious effect of smoking on plasma lipoprotein metabolism significant even in young smokers, which could partly explain the later incidence of atherosclerotic vascular disease in this group.

Adult↗
PubMed1986

Plasma cholesterol metabolism in end-stage renal disease. Difference between treatment by hemodialysis or peritoneal dialysis.

Plasma cholesterol metabolism was investigated in normotriglyceridemic patients with end-stage renal disease treated by hemo- or continuous ambulatory peritoneal dialysis (CAPD), and compared with that in a control group with normal renal function. A reversed net transport of free cholesterol from plasma to cultured fibroblasts, as well as greatly reduced levels of plasma cholesterol esterification and cholesterol ester transfer rates to low and very low density lipoproteins (LDL and VLDL), was found in the hemodialysis group compared to the controls. The LDL and VLDL contained increased amounts of free cholesterol and inhibited cholesterol ester transfer when recombined with control plasma. The LDL triglyceride content was doubled in the hemodialysis group, whereas cholesterol esters were decreased. Patients treated by CAPD, in marked contrast, had cholesterol metabolic rates that were within the normal range, as well as normal lipoprotein composition.

Apolipoprotein A-I↗
PubMed1986

Distribution of apolipoprotein E in the plasma of insulin-dependent and noninsulin-dependent diabetics and its relation to cholesterol net transport.

Noninsulin-dependent diabetics, whose plasma contained no detectable beta-VLDL (very low density lipoprotein), had a proportion (0.23 +/- 0.04) of plasma apolipoprotein E in the form of an abnormal lipoprotein not recognized by antibodies to apoB-100 from LDL (low density lipoprotein) or apoA-I from HDL (high density lipoprotein). This lipoprotein, abnormally rich in free cholesterol and apoE, had a calculated particle density within the low density lipoprotein range. It competed with LDL at the apoB,E receptor of normal fibroblasts and stimulated cholesteryl ester accumulation in mouse peritoneal macrophages. However, it did not compete with the binding of labeled rabbit beta-VLDL to macrophages. A much lower proportion of apoE (0.04 +/- 0.03) was in this form in the plasma of patients with insulin-dependent diabetes who had a comparable degree of hyperglycemia. The diabetic lipoprotein was absent in normoglycemic control subjects. The net transport of cholesterol from cell membranes to the plasma of noninsulin-dependent diabetics (and to a lesser extent, insulin-dependent diabetics) was inhibited relative to control values, and the magnitude of this inhibition was well correlated with the concentration of the abnormal lipoprotein of diabetes in plasma (r = 0.66 and 0.75, respectively). These findings suggest that diabetic plasma contains an abnormal and novel low density lipoprotein that mediates the abnormal cholesterol transport characteristic of human diabetes mellitus.

Apolipoproteins↗
PubMed1985

Effects of postprandial lipemia on plasma cholesterol metabolism.

Cholesterol net transport, esterification, and cholesteryl ester transfer have been determined in plasma during fasting, and postprandially, after a high fat-cholesterol meal. Significant rises in plasma triglyceride, phospholipid, and free cholesterol were associated with increases in cholesterol net transport, esterification, and transfer (all P less than 0.005), which were well correlated in individual subjects (r greater than 0.60). Essentially, the whole of free cholesterol required for such increased esterification was derived from cell membranes, when cultured fibroblasts were present, despite the increased level of free cholesterol in postprandial plasma; most of the additional cholesteryl ester generated was transferred to the low and very low density lipoproteins (LDL and VLDL) of plasma. Postprandial LDL (the major carrier of free and ester cholesterol and phospholipids among the acceptor lipoproteins) contained significantly decreased ratios of free cholesterol to phospholipid (P less than 0.001), which may modulate the increased transfer of cholesteryl ester to VLDL and LDL. These data suggest that the presence of postprandial acceptor lipoproteins in plasma may play an important role in stimulating the "reverse" transport of cholesterol from peripheral cells for hepatic degradation, which is effective even after the ingestion of dietary cholesterol.

Adult↗
PubMed1985

Comparison of cholesterol transport in pulmonary, peritoneal, and blood-derived macrophages from normo- and hypercholesterolemic rabbits.

The influx and efflux components of cholesterol transport were separately determined in pulmonary, peritoneal, and monocyte-derived macrophages from rabbits fed a diet containing either 4.5% fat or 4.5% fat plus 2% cholesterol. Both influx and efflux in pulmonary macrophages increased with increasing concentration of either normal or hypercholesterolemic serum in the medium. The mass of cholesterol entering the macrophages continued to increase beyond the mass of cholesterol effluxed, leading to an increase in cholesterol mass. Similar results were obtained with peritoneal macrophages. Cholesterol-enriched peritoneal macrophages in most cases had a net efflux of sterol when incubated with normocholesterolemic serum. Pulmonary and peritoneal macrophages from cholesterol-fed rabbits tended to have slower sterol influx and a slightly faster sterol efflux than pulmonary and peritoneal macrophages from control rabbits, but the combined effect of these mechanisms did not prevent these macrophages from accumulating sterol ester from hypercholesterolemic serum. Hypercholesterolemic rabbit serum was fractionated by heparin-Sepharose affinity chromatography into a beta-VLDL-deficient nonadsorbed fraction, which had very little effect on pulmonary macrophage sterol content, and an adsorbed beta-VLDL-containing fraction which promoted a large increase in macrophage sterol. As with unfractionated hypercholesterolemic serum, macrophages incubated with the adsorbed beta-VLDL-containing fraction accumulated large amounts of cellular sterol. Monocyte-macrophages cultured in vitro for 21 hr, in contrast to extravascular macrophages, closely regulated their cellular sterol, primarily by limiting the rate of sterol influx.

Animals↗
PubMed1984

Abnormal lecithin:cholesterol acyltransferase activation by a human apolipoprotein A-I variant in which a single lysine residue is deleted.

An apolipoprotein (apo) A-I variant that has a relative charge of -1 compared to normal apo-A-I on isoelectric focusing gels has been identified in five unrelated families as a result of screening a large number of individuals. The cause of the electrophoretic abnormality has been examined by analyzing the variant apo-A-I structure. The evidence suggests that a single amino acid, lysine 107, has been deleted in the variant apo-A-I of all affected individuals studied from these families, with the remainder of the variant apo-A-I sequence being unaffected. The deletion of this single basic amino acid residue is sufficient to account for the charge difference between the variant and normal apo-A-I as seen on isoelectric focusing gels. This variant, previously referred to as A-I-Marburg or A-I-Münster-2, can now be designated by the structural abnormality apo-A-I(Lys107----0). The evidence from extensive pedigree analysis suggests the likelihood that the deletion mutant gene is allelic to the normal apo-A-I gene. At the same time, the kindred analyses have failed to yield a lipid abnormality that can be unequivocally related to the presence of this deletion mutant of apo-A-I. However, all subjects expressing apo-A-I(Lys107----0) also express normal apo-A-I, so that any abnormality caused by the variant apo-A-I might be adequately compensated for by the normal apo-A-I. To examine directly the functional consequence of the lysine deletion, the isolated variant was tested in vitro for its ability to activate lecithin:cholesterol acyltransferase, the principal cholesterol-esterifying enzyme in plasma. It was found that apo-A-I(Lys107----0) is deficient in its ability to activate lecithin:cholesterol acyltransferase, having only 40-60% of the cofactor activity of normal apo-A-I. The cofactor activity of the pro-apo-A-I component of the variant was also reduced to about 60% of either normal A-I or normal pro-apo-A-I. The functional defect is probably related to a disruption in the secondary and/or tertiary structure of the protein caused by the deletion of lysine 107 in the primary structure.

Adult↗
PubMed1984

Increased free cholesterol in plasma low and very low density lipoproteins in non-insulin-dependent diabetes mellitus: its role in the inhibition of cholesteryl ester transfer.

Recombination of low and very low density lipoproteins (VLDL and LDL) from normal subjects with plasma from patients with non-insulin-dependent diabetes mellitus significantly increased the reduced rate of transfer of cholesteryl ester to these lipoproteins, which is characteristic of diabetic plasma, whereas diabetic VLDL and LDL reduced cholesteryl ester transfer rates in normal plasma. VLDL and LDL from diabetic plasma had an increased ratio of free cholesterol to phospholipid compared to normal, and unlike normal VLDL and LDL spontaneously lost free cholesterol to high density lipoprotein. These data suggest that the block to cholesteryl ester transfer to these lipoproteins in non-insulin-dependent diabetes is mediated by their increased free cholesterol content and may be related to the increased risk of these patients for developing atherosclerosis.

Cholesterol↗
PubMed1984

Evidence for the distribution of apolipoprotein E between lipoprotein classes in human normocholesterolemic plasma and for the origin of unassociated apolipoprotein E (Lp-E).

The distribution of apoE between the major lipoprotein classes of normocholesterolemic plasma has been determined by molecular sieve chromatography, immunoaffinity chromatography, preparative ultracentrifugation, and polyanionic precipitation. Highly comparable values were obtained for the first two procedures (correlation coefficient (r) = 0.958), while the other procedures gave recoveries of apoE in high density lipoprotein that were respectively higher and lower, although total recoveries of apoE were essentially complete in each case. Immunoaffinity chromatography under the conditions described was not accompanied by detectable dissociation or redistribution of apoE. By immunoaffinity chromatography, all the apoE of native plasma was present in the form of complexes also containing either apoA-I or apoB. However, both ultracentrifugation and polyanionic precipitation methods of lipoprotein fractionation dissociated substantial proportions of apoE into both lipid-rich and lipid-poor forms that were unassociated with other apolipoproteins. These forms were derived mainly or exclusively from the dissociation of apoE from lipoproteins containing apoB, while apoE bound to apoA-I was dissociated by neither procedure. When lipoproteins were adsorbed on immobilized antibodies to apoA-I or apoB and dissociated with 3 M NaCNS, the apoE and apoA-I remained associated while the complex of apoB and apoE was substantially dissociated. These results suggest that immunoaffinity chromatography accurately determines apoE distribution in plasma. The results on the in vitro generation of unassociated apoE (Lp-E) are discussed in terms of the "family" concept of lipoprotein structure.

Apolipoprotein A-I↗
PubMed1983

Cholesterol net transport, esterification, and transfer in human hyperlipidemic plasma.

Cholesterol esterification, cholesteryl ester transfer between lipoproteins, and cholesterol transport between lipoproteins and cultured cells have been measured in the plasma of 22 patients with primary hyperlipidemia and 10 normolipidemic subjects. In hyperbetalipoproteinemia, increase in plasma low density lipoprotein levels was associated with a reduction of cholesteryl ester transfer rates, and with a reversal of the normal direction of sterol transport between fibroblasts and their plasma culture medium. Instead of net transport from cells to medium there was a net uptake of sterol from plasma by the cells, despite a level of plasma lecithin/cholesterol acyltransferase activity that was within the normal range. In dysbetalipoproteinemia, esterification rates were increased above normal levels, but cholesteryl ester transfer was reduced and the direction of sterol transport between the cells and plasma medium was reversed, as in the hyperbetalipoproteinemic group. In hypertriglyceridemia, those subjects with cardiovascular disease showed a metabolic pattern similar to the hyperbetalipoproteinemic group. The subjects in this group without symptoms of cardiovascular disease showed a normal direction of sterol transport, normal or raised rates of cholesteryl ester transfer between lipoproteins, and an increased rate of sterol esterification in plasma that decreased towards normal levels as plasma triglyceride levels decreased. Despite their quite distinct metabolic patterns there was no consistent difference between the two hypertriglyceridemic groups in triglyceride or cholesterol levels, very low density lipoprotein composition, or electrophoretic or isoelectric focussing patterns. All hypertriglyceridemic subjects with documented cardiovascular disease showed reversed cell-plasma sterol transport and all subjects without such disease showed a normal direction of cell-plasma sterol transport. The results of this study indicate major and reproducible abnormalities in plasma cholesterol metabolism in several groups of subjects with genetically distinct hyperlipidemias, who are at risk for atherosclerotic vascular disease. The possible predictive value of sterol metabolic measurements in the analysis of cardiovascular disease is discussed.

Adult↗
PubMed1982

Evidence for the separation of albumin- and apo A-I-dependent mechanisms of cholesterol efflux from cultured fibroblasts into human plasma.

The role of albumin has been studied in the plasma-mediated efflux of cholesterol from cultured fibroblasts. Immunoaffinity chromatography of plasma on immobilized anti-albumin antibody decreased by 25-50% total efflux catalyzed by plasma. The remainder of the efflux-promoting capacity of plasma was deleted by immunoaffinity chromatography on antibody to apolipoprotein A-I, the major apoprotein of high density lipoprotein. Both components of efflux were saturable with half-saturation at 0.5-1.0% (v/v) plasma. However, the net transport of sterol from cells to medium catalyzed by lecithin:cholesterol acyltransferase, was not reduced by the deletion of the albumin-catalyzed component of efflux. This finding was confirmed with congenitally analbuminemic plasma. These results indicate that efflux to albumin and to high density lipoprotein in plasma represent independent mechanisms; only the latter is coupled to net transport.

Apolipoprotein A-I↗
PubMed1982

Promotion of sterol efflux and net transport by apolipoprotein E in lecithin:cholesterol acyltransferase deficiency.

In the plasma of 4 subjects homozygous for deficiency of lecithin:cholesterol acyltransferase, the level of many apolipoproteins (apo A-I, apo A-II, apo B, apo D) was greatly relative to normal, while that of apo E is increased 5-fold. The lipoprotein complex containing lecithin:cholesterol acyltransferase with apo A-I and apo D in normal plasma is completely absent. The major part of apo E is unassociated with other apolipoproteins. The apoprotein-dependence of sterol efflux and net transport from human skin fibroblasts into plasma was determined by immunoaffinity chromatography. In normal plasma the major component of efflux of sterol radioactivity from labeled fibroblasts was dependent upon unassociated apo A-I. In LCAT-deficient plasma, apoprotein-dependent efflux was largely a function of unassociated apo E. When fibroblasts were incubated with fibrinogen-free unfractionated LCAT-deficient plasma, there was no spontaneous net transport of sterol either into or from the cells, indicating that efflux and influx rates were in balance. When apo E was removed by affinity chromatography, there was net transport from plasma to cells. These findings suggest a novel metabolic role for apo E in the promotion of sterol transport uncoupled to LCAT-activity.

Apolipoproteins↗
PubMed1982

Cholesterol transport between cells and body fluids. Role of plasma lipoproteins and the plasma cholesterol esterification system.

The manner in which cells retain their sterol content is reviewed. Although most of what is known at the molecular level has been defived from studies in continuous cell culture, the findings appear to be broadly applicable to conditions in vivo. The main impetus to this research has come from the potential direct relevance of cell sterol balance to lipid disorders.

Animals↗
PubMed1982

Human noninsulin-dependent diabetes: identification of a defect in plasma cholesterol transport normalized in vivo by insulin and in vitro by selective immunoadsorption of apolipoprotein E.

Plasma cholesterol metabolism in patients with poorly controlled noninsulin-dependent diabetes was characterized by inhibition of cholesterol net transport between cultured cells (fibroblasts) and plasma, inhibition of cholesterol esterification, and inhibition of cholesteryl ester transfer to low and very low density lipoproteins, relative to a normal control group. Plasma from these patients also contained a 2-fold higher level of apolipoprotein E (apo E). Effective control of hyperglycemia with insulin normalized both the parameters of plasma cholesterol metabolism and plasma levels of apo E. Removal of apo E by immunoaffinity chromatography normalized cell-to-plasma cholesterol transport but was without effect on the rate of cholesterol esterification or of cholesteryl ester transfer. These findings suggest that an inhibition in the chain of reactions by which cellular cholesterol is transferred in esterified form to low and very low density lipoproteins is associated with the appearance of an apo E-dependent "shunt" pathway, returning cholesterol from plasma back to the cells and so nullifying the normal cell-to-plasma transport pathway.

Apolipoproteins↗