Increase In Non-esterified Fatty Acids Research Articles

Comparison of effects of platelet-activating factor and tumour necrosis factor-α on lipid metabolism in adrenalectomized rats in vivo

The acute metabolic effects of platelet-activating factor (PAF) and tumour necrosis factor-alpha (TNF-alpha) were compared in sham-operated and adrenalectomized rats. PAF caused hyperglycaemia in sham-operated rats, whereas with TNF-alpha there was a slight decrease in blood glucose. Both PAF and TNF-alpha resulted in marked hypoglycaemia in the adrenalectomized rats. Plasma insulin was depressed (about 50%) by PAF and TNF-alpha in sham-operated rats, whereas in the adrenalectomized rats the already low plasma insulin concentration was not significantly altered. Liver glycogen content was the same in control and treated sham-operated rats, but was considerably decreased (about 50%) in the adrenalectomized rats. In sham-operated rats, PAF and TNF-alpha increased plasma non-esterified fatty acids and triacylglycerols, suggesting increased lipolysis, whereas in adrenalectomized rats there was no significant increase in non-esterified fatty acids with PAF, although it still occurred with TNF-alpha. This suggests that the lipolytic effect of TNF-alpha may be direct, whereas that of PAF is indirect, possibly via increased catecholamines in the sham-operated rats. The stimulation (about 3-fold) of hepatic fatty acid synthesis in vivo by PAF and TNF-alpha in sham-operated rats was still evident in the adrenalectomized rats, although the absolute increase was smaller. PAF, but not TNF-alpha increased (100%) sterol synthesis in adrenalectomized rats. It is concluded that PAF and TNF-alpha can increase hepatic lipogenesis in vivo in the absence of adrenal hormones and in the presence of a low plasma insulin.

Effect of physiological concentrations of insulin and glucagon on the relationship between nonesterified fatty acids availability and ketone body production in humans

To determine the effect of insulin and glucagon on the transformation of nonesterified fatty acids (NEFA) into ketone bodies (KB), we measured simultaneously in normal subjects NEFA and KB kinetics at different NEFA levels in the presence of basal (control test) or increasing insulin concentrations with glucagopenia (somatostatin + insulin infusion, insulin test) and without glucagopenia (somatostatin + insulin + glucagon infusion, glucagon test). NEFA levels were controlled during these tests by an intravenous (IV) infusion of a triglyceride emulsion. During the control test, a moderate increase of NEFA (464 ± 30 to 715 ± 56 μmol/L) increased the percentage of NEFA converted into KB (13.3% ± 1.4% to 26.4% ± 2.1%, P < .05), and there was a linear relationship between this percentage and NEFA levels ( r = .788, P < .01). During the insulin and glucagon tests, the progressive increase in NEFA induced by the triglyceride emulsion infusion was associated, despite the increase of insulinemia, with an increase in KB production rate ( P < .05) and in the proportion of NEFA used for ketogenesis in the presence (8.1% ± 1.2% to 14.2% ± 6.3%, P < .05) and absence (15.7% ± 2.8% to 25.2% ± 3.99%, P < 0.05) of glucagopenia. In both tests, this percentage was always linearly related with NEFA levels ( P < .05) and the slopes of these relationships were comparable to that observed in the control test. However, the fraction of NEFA used for ketogenesis was always higher ( P < .05) during glucagon substitution than in its absence. Last, the study of type 1 diabetic patients with various degrees of metabolic control showed that this percentage of NEFA used for ketogenesis was rather related to increasing NEFA level ( P < .05) than to decreasing insulin concentration ( P>10). In conclusion, within the range of NEFA and insulin attained in this study, we did not obtain evidence for a direct hepatic antiketogenic action of insulin, whereas glucagon appears to stimulate ketogenesis at physiological concentrations.

Do in-vivo suppression and stimulation of lipolysis influence thyroid hormone levels in man?

To determine whether increases in non-esterified fatty acids alter free thyroid hormone and TSH levels, the effect of endogenous activation of lipolysis by insulin-induced hypoglycaemia was examined in seven healthy volunteers pretreated with placebo or acipimox. Whilst levels of non-esterified fatty acid were very different in the two groups, levels of free thyroxine, tri-iodothyronine and TSH were unchanged. Thus, within the range of non-esterified fatty acid levels likely to be seen in clinical practice, any effect on thyroid hormone measurements can be safely ignored.

Effect of maternal fasting on fetal and placental lipid metabolism in swine

This experiment was designed to determine whether mobilizing maternal energy stores by fasting pregnant gilts would promote fetal energy storage by altering placental and fetal lipid metabolism. Pregnant gilts were fed a 15% tallow diet from d 80 to 99 and then fed a basal high-carbohydrate diet (control) or fasted from d 100 to 110 of gestation. Caesarean section was performed on d 110. Fasting caused maternal nonesterified fatty acid (NEFA) levels to increase 7.5-fold, beta-hydroxybutyric acid (beta-HBA) levels to increase 4.8-fold triglyceride (TG) levels to decrease 1.8-fold, and no change in plasma glucose concentration compared with controls. Fasted fetuses had a 1.3-fold increase in NEFA, 1.9-fold decrease in TG, 1.5-fold decrease in glucose, and no change in beta-HBA levels compared with control fetuses. Distribution of NEFA in fetal plasma was different from distribution of NEFA in maternal plasma. Esterification of [14C]-palmitate by maternal placenta and fetal adipose tissue was reduced by fasting, but other parameters of fatty acid metabolism were unaffected. Fasting decreased lipoprotein lipase activity per milligram of protein by 33% in maternal placenta and by 44% in fetal adipose tissue. Glycogen content of fetal liver and skeletal muscle was reduced by fasting pregnant gilts, but there was no detectable effect on percentage of carcass lipid of the fetus. These data suggest that fasting mobilizes maternal fuel stores but that these stores are not effectively used by the placenta or transported to the fetus for storage.

Protein binding of various cephems in healthy subjects and patients with chronic renal failure

This study was employed to investigate whether the serum protein binding of various cephems [cefpiramide (CPM), cefalotin (CET), latamoxef (LMOX)] differ among healthy subjects and patients with chronic renal failure (CRF) by means of in vitro equilibrium dialysis. The protein binding capacities of cephems in patients with CRF (hemodialysis, continuous ambulatory peritoneal dialysis, non-dialysis) decreased significantly compared to those in healthy subjects. The binding capacities correlated directly with total protein, albumin concentration and correlated inversely with blood urea nitrogen and serum creatinine concentration. In the study of protein binding during and after hemodialysis, the binding capacities of CPM and LMOX decreased immediately after dialysis and then increased with the time. However, the binding capacities of CET increased immediately after dialysis and then decreased. The binding capacities of CPM and LMOX correlated inversely with non-esterified fatty acids (NEFA) and those of CET correlated directly with NEFA. In the study of protein binding in pooled sera from healthy subjects with or without palmitic acid (PA), the binding capacities of CPM and LMOX decreased by increasing the concentration of PA, while those of CET increased by increasing PA up to 3 mM. The changes in binding capacity of cephems during and after hemodialysis have been possibly caused by increase of NEFA due to activation of lipase in use of heparin as an anticoagulant. In conclusion, changes in protein binding capacity of cephems in sera from CRF, which should be taken into consideration to avoid possible side effects.

The effect of anoxia on lipid metabolism in isolated adult rat cardiac myocytes

In ischemic myocardium abnormal lipid metabolism results in accumulation of compounds that are deleterious to membrane structural integrity and membrane dependent functions. In this study isolated adult rat ventricular myocytes were used to investigate anoxia-induced alterations in cellular lipid composition and metabolism. Myocyte phospholipid content declined 19% on average during 60 min anoxia and intracellular arachidonic acid increased 3-fold, without affecting myocyte ATP content. Anaerobic incubation in the absence of glucose depleted cellular ATP to 2 nmol/mg protein, elicited a 23% decrease in phospholipids, and reduced triacylglycerol content by 51%. Intracellular levels of C 16–C 22 fatty acids were significantly elevated, especially palmitic and arachidonic acids. Myocytes presented with 0.08 m m [1- 14C]-palmitic or arachidonic acid acylated 85% (25–26 nmol/mg) of the fatty acid taken up into triacylglycerols. Anoxia decreased this esterification by 46–60%. Formation of [ 14C]-CO 2 was also depressed 70–90% by anaerobiosis. The results demonstrate that anoxia stimulates degradation of complex lipids, with a concomitant increase in non-esterified fatty acids, especially arachidonic acid.

Do nonesterified fatty acids displace thyroxin from its plasma binding sites in severe nonthyroidal illnesses?

Severe nonthyroidal illnesses have been associated with increases in nonesterified fatty acids (NEFA) and the dialyzable fraction of thyroxin (T4) in plasma. We have further investigated their possible relationship in severe nonthyroidal illnesses as well as in induced in vivo and in vitro situations involving increased NEFA. We demonstrate that there is no relationship between NEFA and the dialyzable fraction of T4, either in severe nonthyroidal illnesses or in the other situations, unless plasma NEFA concentrations exceed 5 mmol/L in normal persons or 1.7 mmol/L in nonthyroidal illnesses, and that this concentration was not reached in the patients we studied, with one exception. We conclude that NEFA are unlikely to contribute to an inhibition of the binding of T4 to the binding proteins that might be present in plasma of patients with severe nonthyroidal illnesses unless their NEFA concentrations are very high.

Oxfenicine-induced accumulation of lipid in the rat myocardium

Oxfenicine inhibits myocardial metabolism of nonesterified fatty acids (NEFA). The purpose of the present study was to examine the effects of oxfenicine on triglyceride accumulation and the development of histologically visible lipid droplets. The beta-agonist isoproterenol was used to induce elevated arterial NEFA. Four groups of rats were used in the experiment (12 to 14 rats in each group), and each group received two subcutaneous injections, the second injection 25 min after the first, of oxfenicine-isoproterenol, oxfenicine-saline, saline-isoproterenol and saline twice, respectively. One hour after the second injection, the rats were anesthetized, and the hearts from six rats from each group were quickly removed and frozen for later analysis of triglyceride content. From the remaining rats blood samples were drawn for NEFA analysis, and biopsies were taken from the left ventricular wall before the hearts were frozen in liquid nitrogen and prepared for analysis of esters of carnitine and CoA. Quantitative morphometric techniques were used to determine the fractional volume of lipid droplets in myocardial biopsies. Our results show a marked increase in the triglyceride and lipid droplet content in all groups receiving oxfenicine or isoproterenol. The effect was most pronounced after treatment with both drugs. The close association between the increase in triglyceride and lipid droplet supports the notion that the lipid droplets are composed of triglycerides. Our finding that oxfenicine induces lipid droplet accumulation independent of NEFA increase supports the hypothesis that oxfenicine exerts its effect by inhibiting carnitine acyl transferase.

Deinhibition of cardiac Na+-K+-ATPase after exposure to exogenous phospholipase A2.

After 2 h of exogenous phospholipase A2 (PLA2) exposure, membrane phospholipid decreased from 3.22 +/- 0.31 to 1.06 +/- 0.13 mumol/mg (33% of control). All classes of phospholipid, except sphingomyelin, were hydrolyzed, whereas total cholesterol content was unaffected. Increases in nonesterified fatty acids (NEFA) were reflected primarily in oleic (18:1), linoleic (18:2), and arachidonic (20:4). Na+-K+-adenosinetriphosphatase (ATPase) activity was inhibited to 29% of control by 2 h of PLA2 treatment, and this inhibition was reversed (albeit, not completely after 5 min of PLA2 treatment) by removal of the hydrolysis products with 0.1% bovine serum albumin (BSA). In contrast, the apparent binding capacity for [3H]ouabain was not affected by PLA2 treatment. Unmasking of latent [3H]ouabain binding by alamethicin was utilized to estimate changes in the proportion of sealed vesicles present before and after PLA2 treatment. PLA2 treatment resulted in a time-dependent loss of sealed vesicles that paralleled the time course of phospholipid hydrolysis and was not reversed by washing with BSA. These studies demonstrate that cardiac Na+-K+-ATPase activity is inhibited by accumulation of endogenously produced lysophospholipids and NEFA. In contrast, loss of vesicle integrity may result from both accumulation of endogenously produced hydrolysis products and membrane phospholipid depletion.

Hypercholesterolemic effect of indomethacin in the rat

1. 1. The effect of indomethacin on serum lipid constituents of the albino rat was investigated. Indomethacin 1 mg/kg, but not 10 mg/kg body weight, orally administered daily for 3 days, significantly raised total serum cholesterol level from a control value of 58.17 ± 3.40 to 108.50 ± 15.3 ( N = 10; P < 0.05) and free cholesterol level from 52.96 ± 2.21 to 101.17 ± 9.52 ( N = 10; P < 0.05). 2. 2. Indomethacin, 1 mg/kg p.o. daily for 3 days, also raised serum triglycerides from 45.0 ± 7.33 to 118.30 ± 9.05 ( N = 10; P < 0.001), while it reduced phospholipid content from 189.57 ± 58.04 to 98.75 ± 25.85 ( N = 10; P < 0.05). 3. 3. The higher does of indomethacin 10 mg/kg p.o. daily for three days resulted in a significant increase in non-esterified fatty acids, triglycerides and total calcium, while it reduced total bilirubin, phosphorous and total lipid content of rat serum. 4. 4. The results indicate that according to the dose administered, indomethacin could lead to serious derangements in lipid profiles.

Serum cortisol, glucose and lipids in plaice ( Pleuronectes platessa L.) exposed to starvation and aquarium stress

1. 1. Plaice were maintained in the aquarium (11–12†C) during May for 15 days without feeding. 2. 2. Within 48 hr, there was a decline in serum total lipids ( P < 0.001), phospholipids ( P <0.01), triglycerides ( P < 0.001), cortisol ( P < 0.01) and glucose ( P < 0.001), but an increase in nonesterified fatty acids (NEFA; P < 0.01). 3. 3. There was a significant inverse correlation between NEFA and glucose over 15 days ( P < 0.001) and between NEFA and cortisol over the first 5 days ( P < 0.01). Cortisol and glucose showed a significant correlation over 15 days ( P < 0.01). 4. 4. Serum cortisol and glucose were not apparently affected by starvation. 5. 5. Only cortisol provided a sensitive indicator of aquarium disturbance. 6. 6. Exposure of the fish to agitation or reduced O 2 for I hr significantly elevated cortisol ( P < 0.001) but only the latter treatment elevated glucose ( P < 0.01); neither treatment affected the lipids.

Lipoprotein lipases and stress hormones: studies with glucocorticoids and cholera toxin

The intravenous injection of cholera toxin in rats 17 h prior to experimentation results in increased levels of insulin and corticosterone in the blood. This is accompanied by a rise in lipoprotein lipase activity in muscle and a decrease in adipose tissue. Pre- and postheparin blood levels of the enzyme are increased, representing the higher overall muscle activity. Hepatic lipase is decreased by cholera toxin treatment. These enzyme changes are accompanied by increased levels of non-esterified fatty acids, ketone bodies and unesterified cholesterol in the blood, whereas triacylglycerol levels are lowered. The lipoprotein triacylglycerol secretion is not affected by cholera toxin, suggesting increased triacylglycerol removal from the blood. On the other hand the unesterified cholesterol removal may be decreased due to the decreased hepatic lipase activity. Administration of excess glucocorticoid 2 days prior to blood and tissue sampling also resulted in a rise in lipoprotein lipase, a decrease in hepatic lipase activity and an increase of non-esterified fatty acids. In contrast to the effect of cholera toxin, the triacylglycerol levels were increased. Adrenalectomy, whether by inhibition of 11-β-steroid hydroxylase or by surgical intervention, did not abolish the choleratoxin effects. It is concluded that corticosterone increase is not essential to the cholera toxin effects. Corticosterone itself probably causes an increase of cyclic AMP and/or Ca 2+ levels, as is discussed.

Effect of low doses of heparin on the plasma binding of phenytoin and prazosin in normal man.

The effect of low doses of heparin on the binding of phenytoin and prazosin to plasma proteins was evaluated in four normal subjects. Heparin activates the hydrolysis of triglycerides in plasma. The ensuing increase in non-esterified fatty acids (NEFA) was more marked in vitro than in vivo and increased the free fraction (FF) of phenytoin and prazosin in plasma. The higher FF caused a change in the plasma to whole blood ratio (P/B ratio) of both drugs. The changes in FF and P/B ratio after heparin were small, but could be of significance in pharmacokinetic studies.

Hypomagnesemia resulting from adrenaline infusion in ewes: its relation to lipolysis.

Intravenous infusion of adrenaline (40 microgram Kg-1 h-1 for 5 hrs) causes hypomagnesemia in ewes. Hypomagnesemia is increased by phentolamine and inhibited by propranolol. Thyroidectomy, with thyroxine supplementation, does not inhibit the hypomagnesemia caused by adrenaline and phentolamine. Sodium nicotinate (15 mg Kg-1 h-1 for 5 hrs) inhibits the increase in non-esterified fatty acids and hypomagnesemia resulting from infusion of adrenaline and phentolamine. Sodium nicotinate inhibits the increase in non-esterified fatty acids and hypomagnesemia resulting from theophylline infusion (20 mg Kg-1 h-1 for 90 min). It is concluded that an increase in the level of intra-cellular cyclic AMP due to beta adrenergic stimulation by adrenaline or to inhibition of phosphodiesterases by theophylline, results in hypomagnesemia which seems to be correlated with stimulation of lipolysis.

The Influence of Fatty Acids on Serum Thyroxine Determination by Competitive Protein-Binding Radioassay

Thyroxine concentration, determined by competitive protein-binding radioassay (T4(D)), increased in serum stored at 20 degrees C and 37 degrees C. The increase correlated well with the increase in nonesterified fatty acids (NEFA). In vitro addition of NEFA to serum and in vivo increase in NEFA induced by post-prandial heparin injection resulted in a proportional increase in T4(D) values. Protein-bound iodine and thyroxine concentration, as determined by radioimmunoassay, were not influenced by storage and changes in NEFA concentration. NEFA interfere with T4(D), leading to elevated results.

Efficiency of thermoregulation in acutely cold-exposed young and old mice

Mice of different age (4–6 weeks and 1 year) were exposed to 0°. Whereas young animals showed a decrease of liver and muscle glycogen and an increase of non-esterified fatty acids in the serum, old mice did not mobilize their hepatic glycogen and increased their oxygen consumption to much less extent than young animals. Consequently, old mice, in contrast to young mice, were not able to maintain their normal body temperature.

Ineffectiveness of nicotinic acid to impair thermoregulation in cold-exposed mice

Experiments were performed on mice to investigate whether or not nicotinic acid interfered with thermoregulation during exposure to cold. Untreated mice exposed to cold increased their metabolic rate by almost 100%. This was accompanied by a decrease of liver and muscle glycogen and by an increase of non-esterified fatty acids in the serum. About 80% of the animals were able to maintain their body temperature and survive 4 hr cold exposure. After 200 μg/g nicotinic acid glycogenolysis was not impaired but cold-induced lipolysis was partly inhibited. As a consequence the oxygen consumption of the animals could be increased only by 70%. Nevertheless, by compensatory mechanisms the animals were able to maintain their body temperature and survive as well as the controls.

The Metabolic Response to Norepinephrine in Carbon Tetrachloride Poisoned Sheep

The intraruminal administration of carbon tetrachloride to healthy sheep caused a sharp rise in the serum OCT levels. The plasma concentration of non-esterified fatty acids (NEFA) increased, while blood glucose remained unaffected. The glucose response to the intravenous injection of norepinephrine was greatly reduced after carbon tetrachloride administration, indicating a depletion of the liver glycogen. The NEFA response was not altered. As the increase in NEFA caused by carbon tetrachloride was only moderate, a block in lipoproteinsynthesis is discussed as the main factor in the development of the fatty liver.

THE LIPID-MOBILIZING EFFECT OF SOME PITUITARY GLAND PREPARATIONS

ABSTRACT A comparison has been made of some physicochemical and metabolic characteristics of a human growth hormone preparation with somatotrophic and adipokinetic-diabetogenic activity (r.HGH), of a purified r.HGH with potent somatotrophic effect but negligible adipokinetic-diabetogenic effect in the fed animal (t.STH), and a human pituitary-hyperglycaemic and lipid-mobilizing factor (LMF) which was prepared from the crude pituitary extract prior to the preparation of t.STH and was without somatotrophic activity. The t.STH was separated into two bands on polyacrylamide gel electrophoresis, and an additional band was observed for r.HGH in the area of the single band obtained for LMF. The r.HGH, t.STH, and LMF preparations had maximum optical absorption at 278 mμ up to pH 10. At a more alkaline pH the absorption spectrum of t.STH was unchanged, whereas an additional absorption peak at 290 mμ appeared for r.HGH and LMF. Tentative molecular weights determined by Sephadex gel filtration were in the range of 25 000 for r.HGH, 21 000 for t.STH, and 5500 for LMF. The t.STH had a significantly higher growth promoting activity in the tibia test than r.HGH. LMF had no such activity in doses of 1 mg. The adipokinetic effect in fed rabbits was strong for LMF and r.HGH, but negligible for t.STH, which, however, caused an increase of nonesterified fatty acids in animals deprived of food. The in vitro lipolytic effect on human fat, obtained from fasting females, for LMF, r.HGH, and t.STH was on a per weight basis in the ratio of 100:10:1, respectively. In rabbits daily injections of r.HGH and LMF, but not t.STH, induced a hyperglycaemia which continued for 9 and 23 days respectively. Rabbits given daily injections of r.HGH and LMF got a diabetic response of blood glucose after injection of adrenalin and prednisone, although an increased sensitivity to insulin. In contrast to this, a single injection of LMF gave a decreased sensitivity to insulin in the rabbit. Rabbits treated with t.STH behaved as untreated controls. Preparative ultracentrifugation of r.HGH dissolved in physiological saline gave a precipitate with the characteristics of t.STH, and a supernatant with potent hyperglycaemic-adipokinetic effect in rabbits. It was furthermore possible to subdivide r.HGH into t.STH and an adipotrophic component by acetone precipitation and Sephadex gel filtration. It is discussed whether the r.HGH is an aggregation product of t.STH and a hyperglycaemic-adipokinetic agent, or whether the r.HGH is original and made up of these two components.

Influence de l'hormone adrénocorticotrope sur la composition des acides gras non estérifiés du plasma humain normal

Analyses of the fatty acid composition of human plasma non-esterified fatty acids (NEFA) were performed by gas chromatography before and after adrenocorticotropic hormone infusions. The results obtained indicate a significant increase of NEFA, especially of the unsaturated fraction; fatty acid composition of mobilized NEFA differed from that of adipose tissue; it appears that ACTH-sensitive lipase is not the only factor involved in this phenomenon; this hormone is indeed relatively specific for the 1- and 3-triglyceride ester linkages. Therefore, other metabolic pathways are involved, such as monoglyceride lipase and phospholipase activities, undoubtedly associated with selective binding by liver and other tissues.