Acute effect of fatty acids on metabolism and mitochondrial coupling in skeletal muscle

Hirabara, Sandro Massao; Silveira, Leonardo R.; Alberici, Luciane C.; Leandro, Carol V. G.; Lambertucci, Rafael Herling; Polimeno, Gisele C.; Cury-Boaventura, Maria Fernanda; Procópio, Joaquim; Vercesi, Anı́bal E.; Curi, Rui

doi:10.1016/j.bbabio.2005.11.007

Cited by 77 publications

(65 citation statements)

References 55 publications

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“…Notably, mitochondrial uncoupling is characterized by decreased entry of pyruvate into the Krebs cycle in the presence of persistent oxygen consumption, possibly suggesting a shift to the oxidation of other carbon sources (38). Moreover, mitochondrial uncoupling has been demonstrated to promote FAO (39); conversely, FAO has been shown to induce mitochondrial uncoupling (40), at least in part via feed-forward activation of PPARα-regulated UCP3 (41). It is thus tempting to speculate that mitochondrial uncoupling in leukemia cells may represent a shift to unregulated FAO.…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction

Samudio¹,

Harmancey²,

Fiegl³

et al. 2010

J. Clin. Invest.

578

559

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The traditional view is that cancer cells predominately produce ATP by glycolysis, rather than by oxidation of energy-providing substrates. Mitochondrial uncoupling -the continuing reduction of oxygen without ATP synthesis -has recently been shown in leukemia cells to circumvent the ability of oxygen to inhibit glycolysis, and may promote the metabolic preference for glycolysis by shifting from pyruvate oxidation to fatty acid oxidation (FAO). Here we have demonstrated that pharmacologic inhibition of FAO with etomoxir or ranolazine inhibited proliferation and sensitized human leukemia cells -cultured alone or on bone marrow stromal cells -to apoptosis induction by ABT-737, a molecule that releases proapoptotic Bcl-2 proteins such as Bak from antiapoptotic family members. Likewise, treatment with the fatty acid synthase/lipolysis inhibitor orlistat also sensitized leukemia cells to ABT-737, which supports the notion that fatty acids promote cell survival. Mechanistically, we generated evidence suggesting that FAO regulates the activity of Bak-dependent mitochondrial permeability transition. Importantly, etomoxir decreased the number of quiescent leukemia progenitor cells in approximately 50% of primary human acute myeloid leukemia samples and, when combined with either ABT-737 or cytosine arabinoside, provided substantial therapeutic benefit in a murine model of leukemia. The results support the concept of FAO inhibitors as a therapeutic strategy in hematological malignancies. IntroductionMore than half a century ago, Otto Warburg proposed that the origin of cancer cells was closely linked to a permanent respiratory defect that circumvents the Pasteur effect, i.e., the inhibition of anaerobic fermentation by oxygen (1). However, we have recently demonstrated that in leukemia cells, mitochondrial uncoupling - the continuing reduction of oxygen without the synthesis of ATP - could mimic the Warburg effect in the absence of permanent, transmissible alterations to the oxidative capacity of cells (2). This metabolic pattern was observed when leukemia cells were cultured on feeder layers of bone marrow-derived mesenchymal stromal cells (MSCs). MSCs have previously been reported to support both normal and malignant hematopoiesis (reviewed in refs. 3-5) and have become an important component in the in vitro modeling of the bone marrow microenvironment. Leukemia cells cultured on MSC feeder layers demonstrated increased lactate generation, and, most curiously, decreased mitochondrial membrane potential in the presence of a transient (6-8 hour) increase in oxygen consumption. Additionally, this uncoupled phenotype appeared to be associated with the antiapoptotic effect of MSC feeder layers, and we hypothesized a shift away from the complete oxidation of glucose. This concept has already been alluded to by Lynen (6), and by Ronzoni and Ehrenfest in experiments using the prototypical protonophore 2,4-dinitrophenol, and suggests a metabolic shift to fatty acid oxidation (FAO) rather than pyruvate oxidation (2, 7). Although i...

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Section: Discussionmentioning

confidence: 99%

Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction

Samudio¹,

Harmancey²,

Fiegl³

et al. 2010

J. Clin. Invest.

578

559

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“…Os ácidos graxos podem também induzir desacoplamento mitocondrial por um mecanismo independente de UCP (6,39,40). Assim, o desacoplamento mitocondrial, como previamente reportado por um grande número de estudos, aumenta o requerimento de substrato energético (6,37,41). Em função da homologia com a proteína desacopladora UCP-1 do tecido adiposo marrom, UCP-2 e -3 foram inicialmente descritas para exercer função importante na regulação do metabolismo, aumentando a termogênese no tecido muscular esquelético (40) ) é reduzido pelo movimento flip-flop dos ácidos graxos, tendo como intermediária a proteína UCP, aumentando o transporte do ânion ácido graxo da matriz para o espaço intermembrana (Figura 6).…”

Section: As Eros Como Reguladoras Do Metabolismo De Glicose Durante Aunclassified

Regulação do metabolismo de glicose e ácido graxo no músculo esquelético durante exercício físico

Silveira

Pinheiro

Zoppi

et al. 2011

Arq Bras Endocrinol Metab

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SUMMARYThe glucose-fatty acid cycle explains the preference for fatty acid during moderate and long duration physical exercise. In contrast, there is a high glucose availability and oxidation rate in response to intense physical exercise. The reactive oxygen species (ROS) production during physical exercise suggests that the redox balance is important to regulate of lipids/carbohydrate metabolism. ROS reduces the activity of the Krebs cycle, and increases the activity of mitochondrial uncoupling proteins. The opposite effects happen during moderate physical activity. Thus, some issues is highlighted in the present review: Why does skeletal muscle prefer lipids in the basal and during moderate physical activity? Why does glucose-fatty acid fail to carry out their effects during intense physical exercise? How skeletal muscles regulate the lipids and carbohydrate metabolism during the contraction-relaxation cycle? (1) propuseram a existência de uma competição entre glicose e ácidos graxos (AG) como substratos para a síntese de ATP no músculo esquelético, cardíaco e adipócitos. Nesse processo, foi demonstrado que, sob elevada disponibilidade de lipídios, os músculos esqueléticos utilizam predominantemente AG para a síntese e obtenção de ATP. Em contraste, sob elevada disponibilidade de carboidratos, utilizam predominantemente glicose. A questão que surge é qual a importância fisiológica dessa regulação entre glicose e ácidos graxos? Podemos encontrar uma respos-

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“…CAP is a naturally occurring fatty acid; in the deprotonated state (neutral pH), caprylate ion has a well-established metabolic profile as a nutrient in mammals (14). Deprotonating CAP can be accomplished by raising the pH above 4.8 (15); hence, in most physiological environments, CAP will rapidly become deprotonated to a benign nutrient once the local pH increases.…”

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confidence: 99%

Caprylic Acid and Glyceryl Trinitrate Combination for Eradication of Biofilm

Rosenblatt

Reitzel

Raad

2015

Antimicrob Agents Chemother

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There is a growing need for biocompatible, broad-spectrum, nonantibiotic, antimicrobial treatments because of the frequent ineffectiveness of antibiotics against biofilms and the increasing incidence of antibiotic resistance. In this study, we demonstrate rapid and complete biofilm eradication in an in vitro model with synergistic combinations of glyceryl trinitrate and caprylic acid against resistant Gram-positive, Gram-negative, and fungal biofilms.A n estimated 400,000 patients in the United States annually require medical treatment for anal fissures or rectal tears (1, 2). Wounds in microbially contaminated environments (such as the colon and rectum) can be difficult to heal due to the presence of biofilms. Furthermore, surgical site infections associated with implanted devices pose significant medical problems, frequently complicated by microbial biofilm formation on device surfaces (3). This, coupled with the increasing emergence of antibioticresistant biofilms (4), adversely impacts the outcomes of antibiotic wound therapies.Previously, we reported on the synergy of ethanol, citrate, and glyceryl trinitrate (GTN) as a novel nonantibiotic catheter lock solution (5). In other applications involving direct contact with tissues, the use of ethanol above trace concentrations can be undesirable due to potential irritation and cytotoxic responses from certain cell types. Additionally, in applications where bleeding occurs, chelator use can be undesirable, as it can interfere with blood coagulation, an essential step in initiating the healing response. Caprylic acid (CAP) is a medium-chain fatty acid naturally present in human breast milk. CAP has been used intravenously in some total parenteral nutrition formulations (6, 7). It is also readily absorbed following oral administration and yields significant blood concentrations (8). Protonated CAP has been reported to have antimicrobial properties (9, 10). Here, we studied biofilm eradication by the use of medical GTN plus CAP for potential use in medical applications where antimicrobial concentrations of ethanol might cause irritation and where the anticoagulant effects of citrate might be undesirable.The in vitro antimicrobial efficacy of GTN plus CAP was assessed in a well-established biofilm colonization model testing the eradication of biofilm following 2 h of antimicrobial agent exposure. This exposure duration was selected because previous studies showed solutions exhibiting biofilm eradication within 2 h that were also clinically effective (11). Biofilm eradication was assessed for clinical isolates of methicillinresistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), multidrug-resistant Pseudomonas aeruginosa, and Candida albicans, representative of key Gram-positive, Gram-negative, and infectious fungal pathogens (12). Briefly, 1-cm silicone discs were placed in 1 ml of human plasma and incubated overnight at 37°C. The plasma was replaced with 1 ml of 5.5 ϫ 10 5 CFU/ml of challenge organism inoculum and incubated f...

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Acute effect of fatty acids on metabolism and mitochondrial coupling in skeletal muscle

Cited by 77 publications

References 55 publications

Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction

Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction

Regulação do metabolismo de glicose e ácido graxo no músculo esquelético durante exercício físico

Caprylic Acid and Glyceryl Trinitrate Combination for Eradication of Biofilm

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