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PubMed2003

Liver fatty acid binding protein is required for high rates of hepatic fatty acid oxidation but not for the action of PPARalpha in fasting mice.

Liver fatty acid binding protein (L-FABP) has been proposed to limit the availability of long-chain fatty acids (LCFA) for oxidation and for peroxisome proliferator-activated receptor alpha (PPAR-alpha), a fatty acid binding transcription factor that determines the capacity of hepatic fatty acid oxidation. Here, we used L-FABP null mice to test this hypothesis. Under fasting conditions, this mutation reduced beta-hydroxybutyrate (BHB) plasma levels as well as BHB release and palmitic acid oxidation by isolated hepatocytes. However, the capacity for ketogenesis was not reduced: BHB plasma levels were restored by octanoate injection; BHB production and palmitic acid oxidation were normal in liver homogenates; and hepatic expression of key PPAR-alpha target (MCAD, mitochondrial HMG CoA synthase, ACO, CYP4A3) and other (CPT1, LCAD) genes of mitochondrial and extramitochondrial LCFA oxidation and ketogenesis remained at wild-type levels. During standard diet, mitochondrial HMG CoA synthase mRNA was selectively reduced in L-FABP null liver. These results suggest that under fasting conditions, hepatic L-FABP contributes to hepatic LCFA oxidation and ketogenesis by a nontranscriptional mechanism, whereas L-FABP can activate ketogenic gene expression in fed mice. Thus, the mechanisms whereby L-FABP affects fatty acid oxidation may vary with physiological condition.

3-Hydroxybutyric Acid↗
PubMedDate not supplied

Acylation and immunological properties of Mycoplasma gallisepticum membrane proteins.

The acylation of Mycoplasma gallisepticum membrane proteins was studied by electrophoresis after in vivo labelling with different 14C-fatty acids and by chemical analysis. The immunological properties of these proteins were investigated by Western blotting and crossed immunoelectrophoresis. Among the ca. 200 membrane polypeptides resolved by two-dimensional electrophoresis, 35 components (including the major protein p67) were covalently modified with acyl chains. These acylated proteins displayed lower pls than average (5.0-7.4 vs. 5.0-9.0) and proved to be the major membrane protein antigens and immunogens of M. gallisepticum. The apparent selectivity of fatty acid incorporation into proteins was, as suggested by in vivo labelling: palmitic acid (16:0) > myristic acid (14:0) > oleic acid (18:1c) > stearic acid (18:0) > linoleic acid (18:2c). However, the true order of selectivity, as revealed by chemical analysis, proved to be 18:2c > 16:0 > 18:1c > 18:0 > 14:0. More specifically, palmitic acid was the major O-ester-bound fatty acid and linoleic acid the major amide-linked fatty acid. The observed average ratio [O-ester-bound + amide-linked acyl chains]/O-ester-bound chains approximately 1.4 and the presence of S-glycerylcysteine suggest that, in M. gallisepticum, membrane proteins are lipid-modified according to a mechanism identical to that depicted for lipoproteins of Gram-negative eubacteria.

Acylation↗
PubMed1998

Ratios of carbon isotopes in microbial lipids as an indicator of substrate usage.

The occurrence and abundance of microbial fatty acids have been used for the identification of microorganisms in microbial communities. However, these fatty acids can also be used as indicators of substrate usage. For this, a systematic investigation of the discrimination of the stable carbon isotopes by different microorganisms is necessary. We grew 11 strains representing major bacterial and fungal species with four different isotopically defined carbon sources and determined the isotope ratios of fatty acids of different lipid fractions. A comparison of the differences of delta13C values of palmitic acid (C16:0) with the delta13C values of the substrates revealed that the isotope ratio is independent of the growth stage and that most microorganisms showed enrichment of C16:0 with 13C when growing on glycerol. With the exception of Burkholderia gladioli, all microorganism showed depletion of 13C in C16:0 while incorporating the carbons of glucose, and most of them were enriched with 13C from mannose, with the exception of Pseudomonas fluorescens and the Zygomycotina. Usually, the glycolipid fractions are depleted in 13C compared to the phospholipid fractions. The delta13C pattern was not uniform within the different fatty acids of a given microbial species. Generally, tetradecanoic acid (C14:0) was depleted of 13C compared to palmitic acid (C16:0) while octadecanoic acid (C18:0) was enriched. These results are important for the calibration of a new method in which delta13C values of fatty acids from the environment delineate the use of bacterial substrates in an ecosystem.

Aspergillus niger↗
PubMed2005

Behaviour of dioxin in pig adipocytes.

Due to their lipophilic properties, dioxins can be integrated into the lipidic vacuole of adipocytes (fat cells). The aim of this study was to determine the kinetics of incorporation and release of 3H-labelled palmitic acid and 14C-labelled 2,3,7,8-TCDD in isolated adipocytes from pigs. The incorporation of 2,3,7,8-TCDD and palmitic acid was found to be concomitant under conditions of lipogenesis, under the effect of increasing quantities of insulin and in the presence of glucose. Release of these two compounds was found to be dependant on a lipolytic agent (epinephrine). These results suggest the risk of a strong increase of 2,3,7,8-TCDD, induced by lipolysis, in the blood of animals or humans previously exposed to this dioxin.

Adipocytes↗
PubMed1998

4-bromotiglic acid, a novel inhibitor of thiolases and a tool for assessing the cooperation between the membrane-bound and soluble beta-oxidation systems of rat liver mitochondria.

An inhibitor of long-chain 3-ketoacyl-CoA thiolase has been developed as a tool for probing the cooperation between the two fatty acid beta-oxidation systems located in the inner mitochondrial membrane and in the mitochondrial matrix, respectively. 4-Bromotiglic acid was synthesized and found to inhibit palmitoylcarnitine-supported respiration of rat liver mitochondria in concentration-dependent and time-dependent fashions. Complete inhibition of respiration was achieved after incubating coupled mitochondria with 10 microM 4-bromotiglic acid for 2 min. Uncoupled mitochondria were resistant to the toxic effect of the inhibitor. Inhibition of octanoate-supported or octanoylcarnitine-supported respiration was partially reversed when the inhibitor was removed from the incubation medium. Such reversal was not observed with either palmitoylcarnitine or 2-methyldecanoic acid as the respiratory substrate. The severity of the irreversible inhibition declined with decreasing chain length of the acylcarnitine substrate. Of all beta-oxidation enzymes, only thiolases were inactivated by the inhibitor. Under conditions at which acetoacetyl-CoA thiolase and long-chain thiolase were completely inactivated, 3-ketoacyl-CoA thiolase retained some activity. It is concluded that the degradation of palmitic acid and longer-chain fatty acids is initiated by the beta-oxidation system of the inner membrane, whereas fatty acids shorter than palmitic acid can be oxidized to a certain degree by the matrix system alone. The effectiveness of the matrix system increases with decreasing chain length of the substrate.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1974

Effects of Cation Levels of the Nutrient Medium on the Biochemistry of Chlorella: II. Factorial Experiment.

A factorial experiment was designed to study the effects of Mg(2+), K(+), and Na(+) on the growth and biochemistry of Chlorella sorokiniana. Raising Mg(2+) or K(+) concentration in the nutrient medium increased growth rates as well as total N levels and Mg(2+) and K(+) accumulation by the cells. The total N effect was Mg(2+)-dependent-if Mg(2+) was below a certain level in the medium-increasing the K(+) concentration did not raise the total N level of cells. Low nutrient levels of K(+) decreased the levels of unsaturated fatty acids (especially 18:1 and 18:3), while increasing the levels of palmitic acid (16:0), total fatty acids, and total lipid. Increasing nutrient K(+) concentrations were accompanied by increases in levels of some unsaturated fatty acids, with a concomitant reduction in 16:0, total fatty acids and total lipid. Low Mg(2+) levels in the nutrient medium reduced the cellular levels of palmitic acid, total fatty acids, total lipid, and certain unsaturated fatty acids (though this last effect also depended on the nutrient level of K(+)). These relationships indicate that Mg(2+) may be important in the initial steps of fatty acid synthesis, whereas K(+) may be necessary for the formation of certain unsaturated fatty acids. Variations in Na(+) concentration did not have any significant effect on the growth and biochemistry of C. sorokiniana.

Journal Article↗
PubMed1991

Glucose overload and hepatic energy metabolism after resection of the cirrhotic liver in rats.

The effect of glucose hyperalimentation on energy metabolism in the cirrhotic rat liver after 70% hepatectomy was studied. After resection, rats received either 30 kcal/kg per day (group I) or 200 kcal/kg per day (group II) of glucose for 48 h. In both groups, hepatic mitochondrial ATP synthesis was accelerated when palmitic acid was used as substrate and suppressed when pyruvate was used. This suggests that the energy substrate of the remnant liver was principally fatty acids rather than glucose. Hepatic energy charge was within normal limits in group I, but decreased significantly in group II after hepatectomy. An abundance of glucose in the early postoperative period, therefore, caused a hepatic energy derangement by suppressing fatty acids utilization; this suppression was corroborated by the findings of lower immunoreactive glucagon and non-esterified fatty-acid concentrations in group II. To determine optimal glucose administration, the predicted value of glucose disposal rate (GDR) was calculated after an intravenous glucose tolerance test. GDR decreased significantly after hepatectomy and did not increase appreciably even with a large dose of insulin administration. These results suggest that glucose administration should be tailored to the GDR values after resection of the cirrhotic liver.

Adenosine Triphosphate↗
PubMed1989

Posttranslational membrane attachment and dynamic fatty acylation of a neuronal growth cone protein, GAP-43.

Growth cones, the motile apparatus at the ends of elongating axons, are sites of extensive and dynamic membrane-cytoskeletal interaction and insertion of new membrane into the growing axon. One of the most abundant proteins in growth cone membranes is a protein designated GAP-43, whose synthesis increases dramatically in most neurons during periods of axon development or regeneration. We have begun to explore the role of GAP-43 in growth cone membrane functions by asking how the protein interacts with those membranes. Membrane-washing experiments indicate that mature GAP-43 is tightly bound to growth cone membranes, and partitioning of Triton X-114-solubilized GAP-43 between detergent-enriched and detergent-depleted phases indicates considerable hydrophobicity. The hydrophobic behavior of the protein is modulated by divalent cations, particularly zinc and calcium. In vivo labeling of GAP-43 in neonatal rat brain with [35S]methionine shows that GAP-43 is initially synthesized as a soluble protein that becomes attached to membranes posttranslationally. In tissue culture, both rat cerebral cortex cells and neuron-like PC12 cells actively incorporate [3H]palmitic acid into GAP-43. Isolated growth cones detached from their cell bodies also incorporate labeled fatty acid into GAP-43, suggesting active turnover of the fatty acid moieties on the mature protein. Hydrolysis of ester-like bonds with neutral hydroxylamine removes the bound fatty acid and exposes new thiol groups on GAP-43, suggesting that fatty acid is attached to the protein's only two cysteine residues, located in a short hydrophobic domain at the amino terminus. Modulation of the protein's hydrophobic behavior by divalent cations suggests that other domains, containing large numbers of negatively charged residues, might also contribute to GAP-43-membrane interactions. Our observations suggest a dynamic and reversible interaction of GAP-43 with growth cone membranes.

Acylation↗
PubMed1972

Uptake and metabolism of circulating chylomicron triglyceride by rabbit aorta.

To determine if chylomicron triglycerides are taken up and metabolized by the arterial wall, rabbit abdominal aortas were perfused in situ for various times up to 2 hr with blood-buffer containing isotopically labeled substrates. Labeled chylomicrons were obtained by feeding [(3)H]palmitic acid or [(3)H]glyceryl trioleate to rats and rabbits with cannulated thoracic ducts. After aortic perfusion with these chylomicrons, more than 85% of aortic lipid ester radioactivity was in triglyceride; when labeled glycerol or palmitic acid was perfused, most aortic ester lipid radioactivity was in diglycerides and phospholipids. This indicated that, during perfusion with chylomicrons, intact triglyceride molecules were taken up by aorta. The rate of triglyceride fatty acid uptake by the inner avascular segment approached maximal values at low concentrations of perfusate triglyceride fatty acids (2 mm), whereas uptake in the outer capillary perfused segment increased with increasing triglyceride fatty acid concentration (0.4-25 mm). By double-radioisotope techniques it was shown that aortic free fatty acid was derived from both perfusate free fatty acids and from hydrolysis of lipoprotein glycerides within the aortic wall. Uptake of chylomicron triglyceride by perfused aorta was independent of triglyceride hydrolysis, which was quantitatively small.

Animals↗
PubMed1982

Role of lipids in the Neurospora crassa membrane: IV. Biochemical and electrophysiological changes caused by growth on phytanic acid.

Neurospora crassa strain cel, which is deficient in fatty acid synthesis, was grown with phytanic acid supplementation. The temperature dependence of membrane potential is increased by growth on phytanic acid. A temperature change of 40 degrees C produces a change of 184 mV in phytanic acid-grown cells as compared to a 50 mV change for cel grown on palmitic acid or wild-type. Membrane resistance (measured as DC input resistance) of phytanic acid-grown cells did not differ from cel grown on palmitic acid or wild-type. Lipid analysis of cel grown on phytanic acid revealed approximately 7 mole percent phytanic acid incorporation into phospholipids, no change in phospholipid base composition, a reduction of ergosterol content from 80 to 30 percent, and the induction of beta sitosterol, a sterol not usually present in Neurospora. beta sitosterol accounted for approximately 60 percent of the sterol present. Incorporation of 7 mole percent phytanic acid into phospholipids lowers the phase transition temperature by approximately 5 degrees C, and decreases the heat content of the phase transition (delta H) slightly. Results are discussed in relation to Refsum's disease, a human neurological disorder associated with high plasma levels of phytanic acid. It is proposed that high intracellular phytanic acid concentration induces novel sterol synthesis and that the incorporation of the novel sterol into the membrane is responsible for the increased temperature sensitivity of membrane potential. The excitable membrane deficits observed in patients with Refsum's disease may be explained by such a mechanism.

Cell Membrane↗
PubMed1997

Effect of increased uptake of plasma fatty acids by the liver on lipid metabolism in the hepatocellular nuclei.

The nucleus contains different lipids. The aim of the present study was to examine whether increased uptake of free fatty acids by the liver affects lipid metabolism in the hepatocellular nuclei. The experiments were carried out on three groups of Wistar rats: I - male, control; II - male, heparin-treated, and III - female. [14C]-palmitic acid suspended in rat donor serum was administered intravenously 5 and 30 min before tissue samples were taken. Lipids were extracted from isolated liver nuclei and separated into different fractions (phospholipids - PH, monoacylglycerols - MG, diacylglycerols - DG, cholesterol - CH, free fatty acids - FFA, triacylglycerols - TG and cholesterol esters - CHE). It was found that 5 min after administration of the label all isolated nuclear lipid fractions were radioactive. Most of the radioactivity was located in the fraction of PH, TG and FFA. Elevation in the plasma FFA concentration (heparin-treated group) resulted in increased incorporation of [14C]-palmitic acid into the nuclear lipids and changes in its distribution. In the female rats the radioactivity of nuclear lipids was higher than in the male-controls. There were also differences in the percentage distribution of the radioactivity in different lipid fractions between the two groups. The concentration of PH and TG in the nuclei increased only in the heparin-treated but not in the female rats. However, specific activity of the nuclear PH and TG increased in with both groups compared to the male-control group. It is concluded that (a) the blood-borne FFA rapidly enter the nuclear lipid pool and (b) increased uptake of the plasma-borne FFA by the liver affects the nuclear lipid metabolism.

Animals↗
PubMed2002

Altered fatty acid composition of lung surfactant phospholipids in interstitial lung disease.

Deterioration of pulmonary surfactant function has been reported in interstitial lung disease; however, the molecular basis is presently unclear. We analyzed fatty acid (FA) profiles of several surfactant phospholipid classes isolated from large-surfactant aggregates of patients with idiopathic pulmonary fibrosis (IPF; n = 12), hypersensitivity pneumonitis (n = 5), and sarcoidosis (n = 12). Eight healthy individuals served as controls. The relative content of palmitic acid in phosphatidylcholine was significantly reduced in IPF (66.8 +/- 2.5%; means +/- SE; P < 0.01) but not in hypersensitivity pneumonitis (78.5 +/- 1.8%) and sarcoidosis (78.2 +/- 3.1%; control 80.1 +/- 0.7%). In addition, the phosphatidylglycerol FA profile was significantly altered in the IPF patients, with a lower relative content of its major FA, oleic acid, at the expense of saturated FA. In the phosphatidylcholine class, a significant correlation between the impairment of biophysical surfactant function and decreased percentages of palmitic acid was noted. We conclude that significant alterations in the FA profile of pulmonary surfactant phospholipids occur predominantly in IPF and may contribute to the disturbances of alveolar surface activity in this disease.

Adult↗
PubMed1999

Cross-talk mechanisms in the development of insulin resistance of skeletal muscle cells palmitate rather than tumour necrosis factor inhibits insulin-dependent protein kinase B (PKB)/Akt stimulation and glucose uptake.

Insulin resistance in skeletal muscle is one of the earliest symptoms associated with non-insulin-dependent diabetes mellitus (NIDDM). Tumour necrosis factor (TNF) and nonesterified fatty acids have been proposed to be crucial factors in the development of the insulin-resistant state. We here show that, although TNF downregulated insulin-induced insulin receptor (IR) and IR substrate (IRS)-1 phosphorylation as well as phosphoinositide 3-kinase (PI3-kinase) activity in pmi28 myotubes, this was, unlike in adipocytes, not sufficient to affect insulin-induced glucose transport. Rather, TNF increased membrane expression of GLUT1 and glucose transport in these muscle cells. In contrast, the nonesterified fatty acid palmitate inhibited insulin-induced signalling cascades not only at the level of IR and IRS-1 phosphorylation, but also at the level protein kinase B (PKB/Akt), which is thought to be directly involved in the insulin-induced translocation of GLUT4, and inhibited insulin-induced glucose uptake. Palmitate also abrogated TNF-dependent enhancement of basal glucose uptake, suggesting that palmitate has the capacity to render muscle cells resistant not only to insulin but also to TNF with respect to glucose transport by GLUT4 and GLUT1, respectively. Our data illustrate the complexity of the mechanisms governing insulin resistance of skeletal muscle, questioning the role of TNF as a direct inhibitor of glucose homoeostasis in this tissue and shedding new light on an as yet unrecognized multifunctional role for the predominant nonesterified fatty acid palmitate in this process.

Animals↗
PubMed1975

The activity of chaulmoogra acids against Mycobacterium leprae.

The activity of the crude sodium salts of the fatty acids of chaulmoogra oil and of hydnocarpic and chaulmoogric acids against Mycobacterium leprae was studied in mouse footpad infection. Multiplication of the organisms was inhibited when the salts were administered intraperitoneally and subcutaneously 3 times per week, and when chaulmoogric acid was administered intraperitoneally 5 times per week in half the equivalent dose. Dihydrochaulmoogric acid was also active, whereas palmitic acid was not. Hydnocarpic acid administered intraperitoneally once per week in a dose equivalent to half that of the sodium salts of the chaulmoogra fatty acids was not effective. The demonstration that chaulmoogra fatty acids possess activity against M. leprae lends weight to our earlier suggestion that a study of compounds analogous to these acids may yield effective antimicrobial agents with a unique mechanism of action.

Animals↗
PubMed1980

Transfer of long-chain fatty acids to the fetal and neonatal lamb.

The transfer across the ovine placenta of [3H] palmitic acid, 1-[14C] oleic acid, 1-[14C] linoleic acid and 1-[14C] linolenic acid has been studied in chronically catheterized ewes and fetuses using continuous infusion and single injection techniques. No radioactivity was detected in fetal plasma lipids after continuous infusion of isotope into the maternal circulation and a maximum of 0.04% of the injected radioactivity was transferred to the fetal plasma lipids in a 30 min period following the single injection of isotope into the ewe. No detectable radioactivity was transferred to the maternal circulation after injection of isotope into the fetus. The concentration of fetal plasma free fatty acids was very low (less than 50 mumol/1) and that of esterified lipids was about a third of the concentrations in maternal plasma. Two ewes lambed shortly after the infusion of isotope into the maternal circulation and an appreciable amount of radioactivity was subsequently secreted in milk and transferred to the sucking lamb. It was calculated that up to 50% of the radioactivity from 1-[14C] linoleic acid injected into the maternal circulation could have been secreted in milk in the first month of lactation. About 2 g of linoleic acid was secreted in milk daily. It is concluded that the syndesmochorial placenta is virtually impermeable to long chain fatty acids in both directions and that the most important source of linoleic acid for the developing lamb is from milk during the neonatal period.

Animals↗
PubMed1997

Inhibition of fatty acid beta-oxidation in rat brain cultured astrocytes exposed to the neurotoxin 3-nitropropionic acid.

We describe the effects of the neurotoxin 3-nitropropionic acid (3-NPA) on fatty acid oxidation in neonatal rat brain astrocytes in primary culture, using a sensitive assay for beta-oxidation which depends on the release of 3H2O from [9,10(n)-3H]palmitic acid. 3-NPA is a suicide inhibitor of succinate dehydrogenase, a constituent of both Krebs cycle and complex II of the mitochondrial respiratory chain. It is widely distributed in plants and fungi. Neurotoxicity of 3-NPA to humans and animals, leading to selective neuronal cell death, appears mediated by the reduced level of ATP induced by the toxin. We demonstrated that 3-NPA can also impair energy metabolism in astrocytes. Exposure of astroglial cells in culture to 3-NPA leads to inhibition of the release of 3H2O from [9,10(n)-3H]palmitic acid. Addition of 2 mM 3-NPA to the culture medium caused a rapid decrease in beta-oxidation activity, which reached a plateau after 90 min. This inhibition was concentration-dependent. Concentration as low as 0.05 mM for 5 h significantly decreased beta-oxidation activity (25% inhibition). Half-maximal inhibition was obtained after treatment with 0.5 mM 3-NPA, and 3 mM induced a maximal response (63% inhibition) 3-NPA is clearly a potent inhibitor of beta-oxidation activity. We also show that 3-NPA 3 mM inhibits partially complex II (succinate ubiquinone reductase) and aspartate aminotransferase by 60 and 49% after 4 h treatment respectively. It has been shown that fatty acid is the preferred substrate for energy production in cultured astrocytes from developing brain. As astrocytes may also provide substrates alternative for energy metabolism in neurons and oligodendrocytes, it is likely that the inhibition of beta-oxidation by 3-NPA may contribute significantly to the damage induced by this toxin in the central nervous system.

Animals↗
PubMed1990

Fatty acid modulation of antiestrogen action and antiestrogen-binding protein in cultured lymphoid cells.

Nonsteroidal antiestrogens reversibly and specifically inhibited the proliferation of two estrogen receptor-negative lymphoid cell lines (EL4 and Raji) in a dose-dependent manner. [3H]Thymidine incorporation of concanavalin A-stimulated primary splenocytes was also inhibited by 10(-6) M clomiphene (1-[4-(2-diethylaminoethoxy)phenyl]-1,2-diphenyl-2-chloroethylene). The antiproliferative effect could be prevented by the simultaneous presence in the growth medium of 10(-5) M linoleic acid or 10(-5) M arachidonic acid but not by 10(-6) M estradiol. Both lymphoid cell lines had high affinity antiestrogen-binding sites whose affinity could be altered by conditions of growth. Growth of EL4 cells in RPMI 1640 medium supplemented with charcoal-pretreated 5% fetal calf serum (charcoal-stripped medium) resulted in significantly higher affinity (Kd 0.54 nM +/- 0.11 nM; n = 6) than growth in medium supplemented with untreated serum (complete medium) (Kd = 1.68 nM +/- 0.48 nM; n = 6) (p less than 0.001). This change in affinity was partly due to removal of fatty acids from the growth medium by charcoal pretreatment, since addition of 10(-5) M linoleic acid or 10(-5) M gamma-linolenic to charcoal-stripped medium decreased the affinity of the antiestrogen-binding protein. In contrast, growth in 10(-5) M stearic acid or 10(-5) M oleic acid did not significantly alter the affinity of the antiestrogen-binding protein, whereas 10(-5) M palmitic acid significantly increased its affinity. The same fatty acids were also tested for their intrinsic effects on EL4 cell proliferation. Oleic, linoleic and gamma-linolenic acids were growth stimulatory while stearic and palmitic acids were not. Thus linoleic and gamma-linolenic acids whose presence in the growth medium was associated with decreased affinity of [3H]tamoxifen (1-[4-(2-dimethylaminoethoxy)phenyl]-1,2-diphenylbut-1(Z)-ene) binding to the intracellular antiestrogen-binding protein were also growth stimulatory. Unsaturated fatty acids have previously been shown to inhibit binding of [3H]tamoxifen to the antiestrogen-binding protein in a cell-free system. The present observations demonstrate that unsaturated fatty acids also modify the affinity of the antiestrogen-binding protein in intact cells.

Animals↗
PubMed2001

Free fatty acid effects on mitochondrial permeability: an overview.

A variety of experimental conditions elicit increases in mitochondrial permeability that can be differentiated from the classic cyclosporin A (CsA)-sensitive mitochondrial permeability transition (MPT). For example, butylated hydroxytoluene, signal peptides, and the hormone thyroxine have been shown to promote increases in mitochondrial permeability that are CsA-insensitive. Our laboratory has recently demonstrated that palmitic acid, a saturated 16-carbon free fatty acid (FFA), can also open a CsA-insensitive pore. This nonclassic permeability transition (NCPT) is further distinguished by a nonselective dependence on divalent cations and by spontaneous closure. To determine if induction of the NCPT is specific to palmitic acid and to resolve conflicting reports as to the mechanisms by which FFAs alter mitochondrial permeability, we examined in detail mitochondrial swelling induced by FFAs that differ in chain length and degree of saturation. The following results were obtained: (1) In the presence of modest Ca2+ concentrations (75 nmol/mg protein), medium-chain FFAs (C12-C18) were more effective in eliciting mitochondrial swelling than were shorter or longer FFAs; medium-chain alkanols and amines had no effect. (2) Under these conditions, saturated FFAs induced CsA-insensitive swelling with all the characteristics of the NCPT, while unsaturated FFAs triggered the MPT. (3) When matrix Ca2+ concentration was further elevated, unsaturated FFAs triggered the NCPT. (4) Mitochondrial swelling induced by saturated FFAs was inhibited by unsaturated FFAs but not by other saturated FFAs or medium-chain alkanols. These results suggest that ambient conditions can greatly influence the nature of the increase in mitochondrial permeability induced by FFAs. They are also consistent with our earlier proposal that Ca2+ (or Sr2+) binding to FFAs in the inner leaflet of the inner mitochondrial membrane underlies the NCPT.

Animals↗