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At least 1,477 records · Page 82Linked to original sources
PubMed2005

Shotgun lipidomics identifies cardiolipin depletion in diabetic myocardium linking altered substrate utilization with mitochondrial dysfunction.

Diabetic cardiomyopathy is characterized by excessive utilization of fatty acid substrate, diminished glucose transport, and mitochondrial dysfunction. However, the chemical mechanisms linking altered substrate utilization to mitochondrial dysfunction are unknown. Herein, we use shotgun lipidomics and multidimensional mass spectrometry to identify dramatic decreases in the critical mitochondrial inner membrane lipid, cardiolipin, in diabetic murine myocardium (from 7.2 +/- 0.3 nmol/mg of protein in control hearts to 3.1 +/- 0.1 nmol/mg of protein in diabetic myocardium; p < 0.001, n = 7). Moreover, the direct metabolic precursor of cardiolipin, phosphatidylglycerol, was also substantially depleted (2.5 +/- 0.2 nmol/mg of protein in control hearts vs 1.3 +/- 0.1 nmol/mg of protein in diabetic myocardium; p < 0.001, n = 7). Similarly, glycerol 3-phosphate, necessary for the penultimate step in phosphatidylglycerol production, decreased by 58% in diabetic myocardium (from 4.9 +/- 0.9 to 2.2 +/- 0.3 nmol/mg of protein; n = 4). Since Barth's syndrome (a disorder of cardiolipin metabolism) induces mitochondrial dysfunction and cardiomyopathy, and since decreases in cardiolipin content precipitate mitochondrial dysfunction, these results provide a unifying hypothesis linking altered substrate utilization and metabolic flux in diabetic myocardium with altered lipid metabolism, cardiolipin depletion, mitochondrial dysfunction, and resultant hemodynamic compromise.

Animals↗
PubMed1998

Nonesterified fatty acids induce transmembrane monovalent cation flux: host-guest interactions as determinants of fatty acid-induced ion transport.

Nonesterified fatty acids are key intermediates in cellular metabolism whose intracellular concentration is regulated by multiple anabolic, catabolic, and oxidative enzymatic cascades. Herein, we demonstrate that fatty acids induce transmembrane monovalent cation flux with an apparent rate constant kapp = 10(-)4 - 10(-)3 s-1. Fatty acid-induced cation efflux exploits the ionic association of the cation with the carboxylate anion of the fatty acid and the subsequent transmembrane flip-flop of the fatty acid-cation complex. Rates of fatty acid-induced transmembrane cation flux were dependent upon complex host-guest interactions between the fatty acid-cation complex and the phospholipid constituents which comprise the membrane bilayer including (1) the degree of unsaturation of the fatty acid guest and the regiospecificity and stereospecificity of its olefinic linkages; (2) the phospholipid subclass and individual molecular species which constitute the host membrane phospholipids; (3) impedance matching of host and guest hydrophobic characteristics; and (4) the cholesterol content of the membrane bilayer. Arrhenius analysis demonstrated that fatty acid-induced K+ efflux was facilitated largely by changes in the entropy of activation of ion translocation and not the energy of activation. Moreover, Arrhenius analysis demonstrated that the energy of activation of ion translocation was phospholipid subclass specific. For example, arachidonic acid-induced cation efflux in membranes comprised of 16:0-18:1 plasmenylcholine possessed an Ea = 5.3 +/- 0.4 kcal/mol, while that for 16:0-18:1 phosphatidylcholine was 7.2 +/- 0.5 kcal/mol. Electrophysiologic measurements of planar lipid membranes containing 10 mol % arachidonic acid as a substitutional impurity confirmed the ability of physiologically relevant amounts of fatty acid to induce ion translocation with a specific conductance of 2.6 +/- 0.3 microS/cm2. Collectively, these results demonstrate that fatty acids facilitate transmembrane cation flux by an ion carrier type mechanism and suggest that fatty acid-mediated ion transport contributes to the leakage current present in many cell types and thus potentially modulates cellular responsivity during signal transduction where the intracellular content of fatty acids changes dramatically.

Arachidonic Acid↗
PubMed2006

Conjugated dienes as prohaptens in contact allergy: in vivo and in vitro studies of structure-activity relationships, sensitizing capacity, and metabolic activation.

There is a great interest in developing in vitro/in silico methods for the prediction of contact allergenic activity. However, many proposed methods do not take the activation of prohaptens to sensitizers by skin metabolism into account. As a consequence, consumer products containing potent sensitizers could be marketed. To identify prohaptens, studies regarding their structure-activity relationships and the mechanisms of their activation must be conducted. In the present investigation, we have studied the structure-activity relationships for alkene prohaptens. A series of seven alkenes (1-7), all of the same basic structure but with variation in the number and position(s) of the double bond(s), were designed and screened for sensitizing capacity using the murine local lymph node assay. Compounds 1-7 were also incubated with liver microsomes in the presence of glutathione to trap and identify reactive metabolites. The metabolic conversion of three alkenes (9-11) to epoxides (12-15) was also studied along with comparison of their sensitizing capacity. Our results show that conjugated dienes in or in conjunction with a six-membered ring are prohaptens that can be metabolically activated to epoxides and conjugated with GSH. Related alkenes containing isolated double bonds and an acyclic conjugated diene were shown to be weak or nonsensitizers. For the first time, the naturally occurring monoterpenes alpha-phellandrene, beta-phellandrene, and alpha-terpinene were demonstrated to be prohaptens able to induce contact allergy. The difference in sensitizing capacity of conjugated dienes as compared to alkenes with isolated double bonds was found to be due to the high reactivity and sensitizing capacity of the allylic epoxides metabolically formed from conjugated dienes. We recommend that these structure-activity relationship rules are incorporated into in silico predictive databases and propose that the prediction of contact allergenic activity of suspected prohaptens is based on assessment of susceptibility to metabolic activation and chemical reactivity of potential metabolites.

Animals↗
PubMed1987

Metabolism of lysophospholipids in intact rat islets. The insulin secretagogue p-hydroxymercuribenzoic acid impairs lysophosphatidylcholine catabolism and permits its accumulation.

Although recent studies implicate lysophospholipids (lyso-PLs) in stimulus-secretion coupling in the pancreatic islet, almost no data on lyso-PL metabolism therein exist. Therefore, intact rat islets were loaded with insulinotropic and non-toxic concentrations of 1-[14C]palmitoyl-lysophosphatidylcholine (lyso-PC) via transbilayer movement, and its metabolic fate was studied. The time-dependent hydrolysis of lyso-PC to fatty acid (lysophospholipase activity), its conversion to phosphatidylcholine (putative acyltransferase activity) and, to a lesser degree, the appearance of label in phosphatidylethanolamine (putative transacylase or base exchange activity) were observed. p-Hydroxymercuribenzoic acid (PHMB) at 100 microM (a concentration previously demonstrated to elicit potent exocytotic insulin release) inhibited all three activities (by 56, 46 and 75%, respectively) and led to the intracellular accumulation of lyso-PC. Antimycin A inhibited phosphatidylcholine formation but not lysophospholipase activity; lyso-PC did not accumulate, implying that blockade of both of the major metabolic pathways is required to induce a detectable increment in lyso-PC levels. Calculations derived from data using the lowest effective insulinotropic concentration of lyso-PC suggested that increments in lyso-PC accumulation at critical membrane sites of less than 10-15% above basal values are sufficient to trigger insulin release. Since PHMB elicited increments of 50-100% in lyso-PC after its translocation into islets, support is provided for the earlier contention that lyso-PLs mediate the insulinotropic effect of PHMB. In addition, these studies may provide a more precise experimental paradigm for future studies of islet lyso-PL metabolism.

Adenosine Triphosphate↗