Significance of Short Chain Fatty Acid Transport by Members of the Monocarboxylate Transporter Family (MCT).
ABSTRACT Metabolism of short-chain fatty acids (SCFA) in the brain, particularly that of acetate, appears to occur mainly in astrocytes. The differential use has been attributed to transport, but the extent to which transmembrane movement of SCFA is mediated by transporters has not been investigated systematically. Here we tested the possible contribution of monocarboxylate transporters to SCFA uptake by measuring fluxes with labelled compounds and by following changes of the intracellular pH in Xenopus laevis oocytes expressing the isoforms MCT1, MCT2 or MCT4. All isoforms mediated significant transport of acetate. Formate, however, was transported only by MCT1. The contribution of MCT1 to SCFA transport was determined by using phloretin as a high-affinity inhibitor, which allowed a paired comparison of oocytes with and without active MCT1.
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ABSTRACT: Formaldehyde is an environmental pollutant that is also generated in substantial amounts in the human body during normal metabolism. This aldehyde is a well-established neurotoxin that affects memory, learning and behavior. In addition, in several pathological conditions, including Alzheimer's disease, an increase in the expression of formaldehyde-generating enzymes and elevated levels of formaldehyde in brain have been reported. This article gives an overview on the current knowledge on the generation and metabolism of formaldehyde in brain cells as well as on formaldehyde-induced alterations in metabolic processes. Brain cells have the potential to generate and to dispose formaldehyde. In culture, both astrocytes and neurons efficiently oxidize formaldehyde to formate which can be exported or further oxidized. Although moderate concentrations of formaldehyde are not acutely toxic for brain cells, exposure to formaldehyde severely affects their metabolism as demonstrated by the formaldehyde-induced acceleration of glycolytic flux and by the rapid multidrug-resistance protein 1-mediated export of glutathione from both astrocytes and neurons. These formaldehyde-induced alterations in the metabolism of brain cells may contribute to the impaired cognitive performance observed after formaldehyde exposure and to the neurodegeneration in diseases that are associated with increased formaldehyde levels in brain. This article is protected by copyright. All rights reserved.Journal of Neurochemistry 06/2013; · 3.97 Impact Factor
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ABSTRACT: Stem cells are highly proliferating cells that have the potential for differentiation leading to the development of specialized functional cell types. The process of stem cell differentiation requires an increase in the recruitment and population of the undifferentiated stem cells, which are then differentiated to specific functional cell types. Genetic/metabolic transformations in the cellular intermediary energy metabolism are required to provide the bioenergetic, synthetic, and catabolic requirements of the stem cells during this process. However, the identification of the intermediary energy metabolism pathways and their alterations during the proliferation and differentiation of stem cells remain largely unknown; mainly due to the lack of attention and/or required research that focuses on this relationship. In the absence of such information, a full understanding of the factors and conditions required to promote stem cell differentiation leading to development of normal functional metabolic specialized cells cannot be achieved. The purpose of this review is to provide the background and bring attention to the essential relationship of altered cellular intermediary metabolism in the context of the process of stem cell proliferation and differentiation. Citrate metabolism is central to the genetic and metabolic transformation leading to the development of the specialized functional cells. This review identifies the involvement of altered citrate metabolism and the associated genetic alterations of key pathways, enzymes, and transporters; as well as the bioenergetic implications. The importance is emphasized for identification and employment of required conditions to insure that the process of experimental stem cell differentiation results in the development of specialized cells that represent the functional metabolic characteristics and capabilities of their native specialized cells. This is an essential requirement for the successful application of stem cell therapy and regenerative medicine for many pathological conditions.Journal of regenerative medicine & tissue engineering. 05/2013; 2.
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ABSTRACT: Wernicke's encephalopathy-Korsakoff syndrome (WE-KS) is common in alcoholics, caused by thiamine deficiency (TD; vitamin B1) and associated with lesions to the thalamus (THAL). Although TD alone can cause WE, the high incidence in alcoholism suggests that TD and ethanol (EtOH) interact. Mice in control, TD, or EtOH groups alone or combined were studied after 5 or 10 days of treatment. THAL and entorhinal cortex (ENT) histochemistry and mRNA were assessed. Combined EtOH-TD treatment for 5 days (EtOH-TD5) showed activated microglia, proinflammatory gene induction and THAL neurodegeneration that was greater than that found with TD alone (TD5), whereas 10 days resulted in marked THAL degeneration and microglial-neuroimmune activation in both groups. In contrast, 10 days of TD did not cause ENT degeneration. Interestingly, in ENT, TD10 activated microglia and astrocytes more than EtOH-TD10. In THAL, multiple astrocytic markers were lost consistent with glial cell loss. TD blocks glucose metabolism more than acetate. Acetate derived from hepatic EtOH metabolism is transported by monocarboxylic acid transporters (MCT) into both neurons and astrocytes that use acetyl-CoA synthetase (AcCoAS) to generate cellular energy from acetate. MCT and AcCoAS expression in THAL is lower than ENT prompting the hypothesis that focal THAL degeneration is related to insufficient MCT and AcCoAS in THAL. To test this hypothesis, we administered glycerin triacetate (GTA) to increase blood acetate and found it protected the THAL from TD-induced degeneration. Our findings suggest that EtOH potentiates TD-induced THAL degeneration through neuroimmune gene induction. The findings support the hypothesis that TD deficiency inhibits global glucose metabolism and that a reduced ability to process acetate for cellular energy results in THAL focal degeneration in alcoholics contributing to the high incidence of Wernicke-Korsakoff syndrome in alcoholism.Alcoholism Clinical and Experimental Research 10/2013; · 3.42 Impact Factor