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Interactions in vivo between oxidation of non-esterified fatty acids and gluconeogenesis in the newborn rat.

ABSTRACT: Metabolic interactions between fatty acid oxidation and gluconeogenesis were investigated in vivo in 16h-old newborn rats under various nutritional states. As the newborn rat has no white adipose tissue, starvation from birth induces a low rate of hepatic fatty acid oxidation. Hepatic gluconeogenesis in inhibited in the starved newborn rat when compared with the suckling rat, which receives fatty acids through the milk, at the steps catalysed by pyruvate carboxylase and glyceraldehyde 3-phosphate dehydrogenase. These inhibitions are rapidly reversed by triacylglycerol feeding. Inhibition of fatty acid oxidation by pent-4-enoate in the suckling animal mimics the effect of starvation on the pattern of hepatic gluconeogenic metabolites. It is concluded that, in the newborn rat in vivo, hepatic fatty acids oxidation can increase the gluconeogenic flux by providing the acetyl-CoA necessary for the reaction catalysed by pyruvate carboxylase and the reducing equivalents (NADH) to displace the reversible reaction catalysed by glyceraldehyde 3-phosphate dehydrogenase in the direction of gluconeogenesis.

SUBMITTER: Ferre P

PROVIDER: S-EPMC1161341 | biostudies-other | 1979 Aug

REPOSITORIES: biostudies-other

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Regulation of fibrinolysis by non-esterified fatty acids.

Project description:The ability of oleic acid to modulate fibrinolysis was measured by following the urokinase-mediated and plasminogen-dependent cleavage of 125I-labelled fibrin clots. Oleic acid levels within the physiological range exerted a concentration-dependent inhibition of urokinase-mediated fibrinolytic activity. SDS/PAGE revealed that oleic acid enhances urokinase activity but simultaneously increases the autolytic cleavage of the newly formed low-molecular-mass subunit of plasmin. Oleic acid-induced cleavage of this subunit containing the catalytic site of plasmin was suppressed by the plasmin substrate H-D-valyl-L-leucyl-L-lysine-p-nitroanilide (S-2251) and was prevented by alpha 2-antiplasmin. A concentration-dependent inhibition of the activity of purified plasmin on 125I-labelled fibrin clot was also observed; 93% and 50% inhibition was noted with 150 microM and 32 microM oleic acid respectively. Oleic acid at 200 microM also effectively displaced plasmin prebound to a polylysine-Sepharose column. Examination of the fatty acid specificity showed that a minimal chain length of 16 carbon atoms and the presence of at least one double bond, preferably in a cis configuration, were required for inhibition of the fibrinolytic activity of plasmin. Oleic acid at a concentration that produced only a minimal inhibition of plasmin activity induced a marked inhibition by palmitic acid, while palmitic acid alone is ineffective. The findings suggest that oleic acid stimulates plasminogen activation and modulates the fibrinolytic and autolytic activities of plasmin.

| S-EPMC1138149 | biostudies-other

Individual non-esterified fatty acids and incident atrial fibrillation late in life.

Project description:ObjectiveObesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Expansion of fat depots is associated with increased circulating total non-esterified fatty acids (NEFAs), elevated levels of which are associated with incident AF. We undertook comprehensive serum measurement of individual NEFA to identify specific associations with new-onset AF late in life.MethodsThe present study focused on participants with available serum and free of AF selected from the Cardiovascular Health Study, a community-based longitudinal investigation of older US adults. Thirty-five individual NEFAs were measured by gas chromatography. Cox regression was used to evaluate the association of individual NEFAs with incident AF.ResultsThe study sample included 1872 participants (age 77.7±4.4). During median follow-up of 11.3 years, 715 cases of incident AF occurred. After concurrent adjustment of all NEFAs and full adjustment for potential confounders, higher serum concentration of nervonic acid (24:1 n-9), a long-chain monounsaturated fatty acid, was associated with higher risk of AF (HR per SD: 1.18, 95% CI 1.08 to 1.29; p<0.001). Conversely, higher serum concentration of gamma-linolenic acid (GLA) (18:3 n-6), a polyunsaturated n-6 fatty acid, was associated with lower risk of AF (HR per SD: 0.81, 95% CI 0.71 to 0.94; p=0.004). None of the remaining NEFAs was significantly associated with AF.ConclusionsAmong older adults, serum levels of non-esterified nervonic acid were positively associated, while serum levels of non-esterified GLA were inversely associated, with incident AF. If confirmed, these results could offer new strategies for AF prevention and early intervention in this segment of the population at highest risk.

| S-EPMC8607526 | biostudies-literature

Metabolic fate of non-esterified fatty acids in isolated hepatocytes from newborn and young pigs. Evidence for a limited capacity for oxidation and increased capacity for esterification.

Project description:In hepatocytes isolated from 48 h-old starved of suckling newborn pigs or from 15-day-old starved piglets, the rate of ketogenesis from oleate or from octanoate is very low. This is not due to an inappropriate fatty acid uptake by the isolated liver cells, but results from a limited capacity for fatty acid oxidation. Some 80-95% of oleate taken up is converted into esterified fats, whatever the age or the nutritional conditions. Three lines of indirect evidences suggest that fatty acid oxidation is not controlled primarily by malonyl-CoA concentration in newborn pig liver. Firstly, the addition of glucagon does not increase fatty acid oxidation or ketogenesis. Secondly, the rate of lipogenesis is very low in isolated hepatocytes from newborn pigs. Thirdly, the rates of oxidation and ketogenesis from octanoate are also decreased in isolated hepatocytes from newborn and young piglets. The huge rate of esterification of fatty acids in the liver of the newborn pigs probably represents a species-specific difference in intrahepatic fatty acid metabolism.

| S-EPMC1152014 | biostudies-other

Circulating Non-Esterified Fatty Acids as Biomarkers for Fat Content and Composition in Pigs.

Project description:Circulating non-esterified fatty acids (NEFA) can reflect the composition of dietary fat or adipose tissues depending on the fasting conditions. Therefore, circulating NEFA may be valuable as biomarkers for meat quality traits, such as intramuscular fat content and fatty acid composition in finishing pigs. Genetic variants that regulate lipid metabolism can also modulate the circulating NEFA. We conducted an experiment with 150 heavy Duroc pigs to evaluate fluctuations in the circulating NEFA composition due to age, fasting duration and two genetic polymorphisms, one in the leptin receptor (LEPR; rs709596309) and one in the stearoyl-CoA desaturase (SCD; rs80912566) gene. Circulating NEFA were more saturated and less monounsaturated than the subcutaneous and intramuscular adipose tissues. Absolute circulating NEFA content was more influenced by fasting duration than age. The SCD polymorphism did not impact NEFA content or composition. The LEPR polymorphism affected the content but not the fatty acid composition. Circulating oleic acid NEFA content after a short fasting was positively correlated with intramuscular fat content and, after a long fasting, with intramuscular oleic acid content. We conclude that circulating NEFA reflect environmental and genetic metabolic changes but are of limited value as biomarkers for intramuscular fat content and fatty acid composition.

| S-EPMC7913534 | biostudies-literature

Type 2 diabetes associated changes in the plasma non-esterified fatty acids, oxylipins and endocannabinoids.

Project description:Type 2 diabetes has profound effects on metabolism that can be detected in plasma. While increases in circulating non-esterified fatty acids (NEFA) are well-described in diabetes, effects on signaling lipids have received little attention. Oxylipins and endocannabinoids are classes of bioactive fatty acid metabolites with many structural members that influence insulin signaling, adipose function and inflammation through autocrine, paracrine and endocrine mechanisms. To link diabetes-associated changes in plasma NEFA and signaling lipids, we quantitatively targeted >150 plasma lipidome components in age- and body mass index-matched, overweight to obese, non-diabetic (n?=?12) and type 2 diabetic (n?=?43) African-American women. Diabetes related NEFA patterns indicated ?60% increase in steroyl-CoA desaturase activity and ?40% decrease in very long chain polyunsaturated fatty acid chain shortening, patterns previously associated with the development of nonalcoholic fatty liver disease. Further, epoxides and ketones of eighteen carbon polyunsaturated fatty acids were elevated >80% in diabetes and strongly correlated with changes in NEFA, consistent with their liberation during adipose lipolysis. Endocannabinoid behavior differed by class with diabetes increasing an array of N-acylethanolamides which were positively correlated with pro-inflammatory 5-lipooxygenase-derived metabolites, while monoacylglycerols were negatively correlated with body mass. These results clearly show that diabetes not only results in an increase in plasma NEFA, but shifts the plasma lipidomic profiles in ways that reflect the biochemical and physiological changes of this pathological state which are independent of obesity associated changes.

| S-EPMC3493609 | biostudies-literature

Cocultured porcine granulosa cells respond to excess non-esterified fatty acids during in vitro maturation.

Project description:BackgroundNon-esterified fatty acids (NEFAs) are one of the main lipid components of follicular fluid at concentrations that depend on circulating levels. Elevated levels of NEFAs impair oocyte quality, development potential, and may subsequently influence the metabolism and reproductive fitness of offspring. Granulosa cells (GCs) are the follicular cells that are closely communicating with the oocyte. However, the responses of GCs exposed to high levels of NEFAs when cocultured with cumulus-oocyte complexes (COCs), and how they attenuate the negative effects of NEFAs on oocytes, are unclear.ResultsTo better understand this protective effect, monolayers of porcine GCs were cocultured with COCs during in vitro maturation (IVM) in the presence of elevated levels of NEFAs. Genomic expression analysis was conducted to explore the responses of the GCs to the elevated levels of NEFAs. After limma algorithm analysis, 1,013 genes were differentially expressed between GCs cultured with and without elevated NEFAs. Among them, 438 genes were upregulated and 575 were downregulated. The differentially expressed genes were enriched in pathways related to metabolism, inflammation, and epithelial-mesenchymal transition.ConclusionsThe pathways and upstream regulators suggested that the cocultured GCs responded to the elevated NEFAs with (1) inhibition of the transition from granulosa to luteal cell, (2) interactions of metabolism change, anti-inflammation, mitochondrial function, and cell transition, (3) intercommunication with cocultured COCs of anti-inflammatory factors.

| S-EPMC8554973 | biostudies-literature

Non-Esterified Fatty Acids Profiling in Rheumatoid Arthritis: Associations with Clinical Features and Th1 Response.

Project description:ObjectivesSince lipid compounds are known to modulate the function of CD4+ T-cells and macrophages, we hypothesize that altered levels of serum non-esterified fatty acids (NEFA) may underlie rheumatoid arthritis (RA) pathogenesis.MethodsSerum levels of NEFA (palmitic, stearic, palmitoleic, oleic, linoleic, γ-linoleic, arachidonic -AA-, linolenic, eicosapentaenoic -EPA- and docosahexaenoic -DHA-) were quantified by LC-MS/MS after methyl-tert-butylether (MTBE)-extraction in 124 RA patients and 56 healthy controls (HC). CD4+ phenotype was studied by flow cytometry. TNFα, IL-8, VEGF, GM-CSF, IFNγ, IL-17, CCL2, CXCL10, leptin and resistin serum levels were quantified by immunoassays. The effect of FA on IFNγ production by PBMC was evaluated in vitro.ResultsLower levels of palmitic (p<0.0001), palmitoleic (p = 0.002), oleic (p = 0.010), arachidonic (p = 0.027), EPA (p<0.0001) and DHA (p<0.0001) were found in RA patients, some NEFA being altered at onset. Cluster analysis identified a NEFA profile (hallmarked by increased stearic and decreased EPA and DHA) overrepresented in RA patients compared to HC (p = 0.002), being associated with clinical features (RF, shared epitope and erosions), increased IFNγ expression in CD4+ T-cells (p = 0.002) and a Th1-enriched serum milieu (IFNγ, CCL2 and CXCL10, all p<0.005). In vitro assays demonstrated that imbalanced FA could underlie IFNγ production by CD4+ T-cells. Finally, changes on NEFA levels were associated with clinical response upon TNFα-blockade.ConclusionAn altered NEFA profile can be found in RA patients associated with clinical characteristics of aggressive disease and enhanced Th1 response. These results support the relevance of lipidomic studies in RA and provide a rationale for new therapeutic targets.

| S-EPMC4972416 | biostudies-literature

Evidence for dissociation of gluconeogenesis stimulated by non-esterified fatty acids and changes in fructose 2,6-bisphosphate in cultured rat hepatocytes.

Project description:In order to examine the role of fructose 2,6-bisphosphate (Fru-2,6-P2) in non-esterified-fatty-acid-stimulated gluconeogenesis, Fru-2,6-P2 levels were measured in cultured rat hepatocytes under conditions mimicking the fasted state. After addition of either 1.5 mM-palmitate or 10 nM-glucagon, [U-14C]lactate incorporation into glucose increased 2-fold, but only glucagon suppressed Fru-2,6-P2. Prevention of palmitate oxidation with a carnitine palmitoyltransferase-I inhibitor (2-bromopalmitate) diminished glucose production and Fru-2,6-P2 levels. Addition of exogenous glucose to the media increased Fru-2,6-P2 in a dose-related manner, which was further augmented by addition of palmitate. When Fru-2,6-P2 levels were examined in cells cultured under conditions mimicking the fed state (significantly higher basal Fru-2,6-P2 levels and lower glucose production), palmitate oxidation was associated with a significant fall in Fru-2,6-P2. In conclusion, the present studies have demonstrated a dissociation between fatty-acid-stimulated gluconeogenesis and changes in Fru-2,6-P2 in cultured rat hepatocytes. Further experiments suggest that the accumulation of intracellular hexose 6-phosphate as a result of fatty-acid-stimulated gluconeogenesis masks a putative inhibitory effect of fatty acids on Fru-2,6-P2 concentrations.

| S-EPMC1132091 | biostudies-other

The serum competitor of oestrogen--rat alpha 1-foetoprotein interactions. Identification as a mixture of non-esterified fatty acids.

Project description:The novel endogenous serum ligands of rat alpha 1-foetoprotein previously demonstrated in different mammalian sera were identified by g.l.c.--mass-spectrometric methods as a mixture of non-esterified long-chain and predominantly unsaturated fatty acids. Detailed comparative analyses of these ligands extracted from foetal- and pregnant-rat sera, rat amniotic fluid and foetal human sera are presented. We also show that an important fraction of these ligands remains associated with the rat alpha 1-foetoprotein after purification; analyses are given for the composition of this lipid moiety of the foetoprotein. The physiological relevance of these results is discussed.

| S-EPMC1162471 | biostudies-other

The Interplay between Non-Esterified Fatty Acids and Plasma Zinc and Its Influence on Thrombotic Risk in Obesity and Type 2 Diabetes.

Project description:Thrombosis is a major comorbidity of obesity and type-2 diabetes mellitus (T2DM). Despite the development of numerous effective treatments and preventative strategies to address thrombotic disease in such individuals, the incidence of thrombotic complications remains high. This suggests that not all the pathophysiological mechanisms underlying these events have been identified or targeted. Non-esterified fatty acids (NEFAs) are increasingly regarded as a nexus between obesity, insulin resistance, and vascular disease. Notably, plasma NEFA levels are consistently elevated in obesity and T2DM and may impact hemostasis in several ways. A potentially unrecognized route of NEFA-mediated thrombotic activity is their ability to disturb Zn2+ speciation in the plasma. Zn2+ is a potent regulator of coagulation and its availability in the plasma is monitored carefully through buffering by human serum albumin (HSA). The binding of long-chain NEFAs such as palmitate and stearate, however, trigger a conformational change in HSA that reduces its ability to bind Zn2+, thus increasing the ion's availability to bind and activate coagulation proteins. NEFA-mediated perturbation of HSA-Zn2+ binding is thus predicted to contribute to the prothrombotic milieu in obesity and T2DM, representing a novel targetable disease mechanism in these disorders.

| S-EPMC8471329 | biostudies-literature

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