Inhibitory Effect Of Free Fatty Acids Research Articles

Improved dialytic removal of protein-bound uremic toxins by intravenous lipid emulsion in chronic kidney disease rats.

Protein-bound uremic toxins (PBUTs) have received extensive attention, as their accumulation leads to pleiotropic toxic biological effects, while the removal of these solutes by conventional dialysis therapies is severely hampered. This study aimed to examine whether increased removal of PBUTs could be achieved with intravenous lipid emulsion (ILE). PBUTs such as 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), p-cresyl sulfate (PCS) and indoxyl sulfate (IS) were spiked with human serum albumin (HSA) solution and the inhibitory effects of free fatty acid (FFA) on the binding of CMPF, PCS and IS to HSA were examined separately in vitro by ultrafiltration. In vitro dialysis of albumin solution was then performed to investigate the effects of fatty acid (FAs) mixtures infusion on the fractional removal of PBUTs. Finally, the inhibitory effect of FFA on the binding of PBUTs to albumin was examined in uremic rats, and blood purification therapy was conducted to calculate the reduction ratio (RR) and the total solute removal (TSR) of solutes. The percentage protein binding of CMPF, PCS and IS decreased significantly with increasing FFAs concentrations, and the inhibitory effect was more remarkable with the addition of oleic acid or linoleic acid than that of eicosapentaenoic acid and docosahexaenoic acid. In vitro infusion of FAs increased the fractional removal of CMPF to 14.40 ± 2.38%. PCS, IS and indole-3-acetic acid removal increased from 8.00 ± 2.43%, 11.68 ± 1.54% and 15.38 ± 3.97%, respectively, at baseline to 28.21 ± 5.99%, 35.42 ± 5.27% and 40.18 ± 5.05%, respectively, when FAs were present. In vivo, rat serum concentrations of free PBUTs were significantly higher in the ILE group than in the control group, and administration of ILE resulted in higher RRs and more TSR for PBUTs after 3 h of hemodialysis (HD) therapy compared with the control group. Administration of ILE effectively increased the dialytic removal of PBUTs. This method could be applied to current HD therapy.

Kinetics of drug binding to human serum albumin: allosteric and competitive inhibition at the benzodiazepine binding site by free fatty acids of various chain lengths

The inhibition of dansylsarcosine (DS) binding at the benzodiazepine binding site of human serum albumin has been studied in the presence of saturated and unsaturated free fatty acids (FFA) of various chain lengths (C6-C20, C18:1, C18:2). In order to determine the mechanism of displacement, velocity constants for association (k2) and dissociation (k-2) and binding constants (KA and KA') have been measured using the stopped-flow method. The inhibitory effect of FFA on DS binding kinetics at site II is dependent of their structure. With increasing amounts of FFA the association velocity constant of DS binding decreases from 520 s-1 (fatty acid free albumin) by a factor of 3-10 and affinity decreases according to FFA chain length. Inhibition is strongest in the presence of caprylic, capric and lauric acid (C8-C12) i.e. with more than one mole FFA per mole albumin, DS association could no longer be measured. Short chain caproic and the long chain FFA C14-C20 showed only a less inhibitory effect since in the presence of a twofold excess k2 ranged between 100 and 200 s-1. Dissociation velocity of DS from the benzodiazepine binding site could be measured in relationship to FFA chain length using ibuprofene, another drug binding at site II. Dissociation velocity constants k-2 remained constant up to 2 moles FFA per mole albumin (k-2 = 16-18 s-1). A rise in k-2 to 70 s(-1) was seen, however, when 2-4 moles capric, lauric, myristic and palmitic (C10-C16) acid were bound, whereas no change was observed when increasing concentrations of caproic, caprylic, stearic and arachic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Coenzyme Q releases the inhibitory effect of free fatty acids on mitochondrial glycerophosphate dehydrogenase.

Data presented in this paper show that the size of the endogenous coenzyme Q (CoQ) pool is not a limiting factor in the activation of mitochondrial glycerophosphate-dependent respiration by exogenous CoQ(3), since successive additions of succinate and NADH to brown adipose tissue mitochondria further increase the rate of oxygen uptake. Because the inhibition of glycerophosphate-dependent respiration by oleate was eliminated by added CoQ(3), our data indicate that the activating effect of CoQ(3) is related to the release of the inhibitory effect of endogenous free fatty acids (FFA). Both the inhibitory effect of FFA and the activating effect of CoQ(3) could be demonstrated only for glycerophosphate-dependent respiration, while succinate- or NADH-dependent respiration was not affected. The presented data suggest differences between mitochondrial glycerophosphate dehydrogenase and succinate or NADH dehydrogenases in the transfer of reducing equivalents to the CoQ pool.

Coenzyme Q releases the inhibitory effect of free fatty acids on mitochondrial glycerophosphate dehydrogenase.

Data presented in this paper show that the size of the endogenous coenzyme Q (CoQ) pool is not a limiting factor in the activation of mitochondrial glycerophosphate-dependent respiration by exogenous CoQ(3), since successive additions of succinate and NADH to brown adipose tissue mitochondria further increase the rate of oxygen uptake. Because the inhibition of glycerophosphate-dependent respiration by oleate was eliminated by added CoQ(3), our data indicate that the activating effect of CoQ(3) is related to the release of the inhibitory effect of endogenous free fatty acids (FFA). Both the inhibitory effect of FFA and the activating effect of CoQ(3) could be demonstrated only for glycerophosphate-dependent respiration, while succinate- or NADH-dependent respiration was not affected. The presented data suggest differences between mitochondrial glycerophosphate dehydrogenase and succinate or NADH dehydrogenases in the transfer of reducing equivalents to the CoQ pool.

Modulation of glucocorticoid binding to rat liver cytosol receptor by lipid-soluble extracts from the serum of AIDS patients.

The total liposoluble extract of sera from AIDS patients, IVC1 and IVD stages, containing cortisol and free fatty acids (FFA) inhibited [3H]dexamethasone binding to a lesser extent than did the same quantity of total liposoluble extract of sera from healthy men. FFA isolated from extracts of AIDS sera by Sephadex LH20 chromatography had less effect on [3H]dexamethasone binding to rat liver glucocorticoid receptor than those extracted from sera of healthy men. These results suggest the presence in sera of AIDS patients of a liposoluble substance which could be limiting the inhibitory effect of FFA on [3H]dexamethasone binding to glucocorticoid receptor by inducing a conformational change in glucocorticoid receptor that could alter the biological action of glucocorticoids. The pathological consequence could be the apparent contradiction of high cortisolemia and clinical symptoms of adrenal insufficiency that have been observed in AIDS patients.

Inhibitory effect of plasma free fatty acids on glucose production in the conscious dog.

We have previously reported that, in conscious, unrestrained dogs in which insulin and glucagon levels were clamped pharmacologically, combined alpha- and beta-adrenergic blockade resulted simultaneously in a fall in plasma free fatty acid (FFA) levels and an increase in glucose production. In this study we have tested the hypothesis that the increase in glucose production observed in the previous study was due to the fall in plasma FFA concentration. Glucose production was measured by means of the primed-constant infusion of [6-3H]- and/or [U-14C]glucose, and insulin and glucagon were clamped at constant levels by means of the infusion of somatostatin, insulin, and glucagon. When no attempt was made to control the FFA levels, combined alpha- and beta-adrenergic blockade significantly decreased plasma FFA levels, and this was associated with a significant increase in the rate of glucose production. However, the glucose production response to adrenergic blockade was entirely prevented by the clamping of FFA levels at a high, constant value by the infusion of a 10% lipid emulsion (Liposyn) and heparin. We conclude that basal adrenergic activity is important in the mobilization of fat but does not directly influence glucose production. Further, there is an inhibitory effect of FFA on glucose production that is unmasked during hormonal control and alpha- and beta-adrenergic blockade.

On a slow inhibitory effect of free fatty acids on the respiratory chain of non-phosphorylating submitochondrial particles from beef heart

Free fatty acids (FFA) exert a variety of inhibitory effects on the energy metabolism of mitochondria. They uncouple the oxidative phosphorylation [l-4], inhibit the ATP-Pi exchange [2,3], stimulate the Mg-dependent ATPase [ 1,2] and act as endogenous ionophores for potassium ions [ 51. Moreover, the CoA-esters of fatty acids are strong inhibitors of the adenine nucleotide translocase [6] and the pyridine nucleotide transhydrogenase system [7]. FFA exhibit an instantaneous multi-site inhibition of the electron transport system of non-phosphorylating submitochondrial particles (ETP) which is relieved or prevented by serum albumin [8,9]. In this report a new inhibitory effect of FFA is described which appears slowly.

Operation of the “Glucose‐Fatty Acid Cycle” during Experimental Elevations of Plasma Free Fatty Acid Levels in Man

Abstract. In order to determine whether increased plasma free fatty acid (FFA) levels inhibit glucose utilization in man, glucose metabolism was studied in 8 normal subjects both under basal conditions and during experimental elevations of plasma FFA concentrations induced by the administration of high fat meals and heparin. A primed constant infusion of 1‐14C‐glucose was used to measure the rate of turnover, the fractional removal rate and the rate of oxidation of plasma glucose under both experimental conditions. Elevations of FFA levels (+117%) were accompanied by a 9% reduction in both the fractional removal rate of glucose and the hepatic glucose production so that glycaemia remained unchanged. The % glucose converted to CO2, and the % CO2 derived from plasma glucose decreased respectively by 13.5% and 21.7%, while unlabelled CO2 production remained unchanged. This reduction in glucose utilization occurred despite a significant rise in insulin concentration indicating that high FFA levels reduce sensitivity to insulin. The tissue implicated in the inhibitory effect of FFA on overall glucose utilization cannot be determined from these experiments but it is suggested that muscle participated in these metabolic changes. These data provide further arguments supporting the view that plasma FFA participate in the regulation of glucose metabolism in man.

Operation of the "glucose-fatty acid cycle" during experimental elevations of plasma free fatty acid levels in man.

Abstract. In order to determine whether increased plasma free fatty acid (FFA) levels inhibit glucose utilization in man, glucose metabolism was studied in 8 normal subjects both under basal conditions and during experimental elevations of plasma FFA concentrations induced by the administration of high fat meals and heparin. A primed constant infusion of 1‐14C‐glucose was used to measure the rate of turnover, the fractional removal rate and the rate of oxidation of plasma glucose under both experimental conditions. Elevations of FFA levels (+117%) were accompanied by a 9% reduction in both the fractional removal rate of glucose and the hepatic glucose production so that glycaemia remained unchanged. The % glucose converted to CO2 and the % CO2 derived from plasma glucose decreased respectively by 13.5% and 21.7%, while unlabelled CO2 production remained unchanged. This reduction in glucose utilization occurred despite a significant rise in insulin concentration indicating that high FFA levels reduce sensitivity to insulin. The tissue implicated in the inhibitory effect of FFA on overall glucose utilization cannot be determined from these experiments but it is suggested that muscle participated in these metabolic changes. These data provide further arguments supporting the view that plasma FFA participate in the regulation of glucose metabolism in man.