Long-chain fatty acids act as protonophoric uncouplers of oxidative phosphorylation in rat liver mitochondria

Schönfeld, Peter; Schild, Lorenz; Kunz, Wolfgang

doi:10.1016/s0005-2728(89)80080-5

Cited by 70 publications

(32 citation statements)

References 32 publications

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“…Moreover high levels of NEFA may increase myocardial oxygen consumption via fruitless cycling of energy wasting reactions, such as repeated cycles of trygliceride synthesis and lipolysis. Furthermore, a protonophoric action of fatty acids has been also shown in vitro 44 , but not in vivo. 45 This effect has been hypothesized to be related to the chain length and degree of saturation of the NEFA 46 , but so far no clear explanation for these putative uncoupling effects of long-chain NEFA has been proposed.…”

Section: Nefa and Gene Expression In Rat Heartmentioning

confidence: 99%

Changes in FAT/CD36, UCP2, UCP3 and GLUT4 gene expression during lipid infusion in rat skeletal and heart muscle

et al. 2002

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OBJECTIVE: It has been reported that an increased availability of free fatty acids (NEFA) not only interferes with glucose utilization in insulin-dependent tissues, but may also result in an uncoupling effect of heart metabolism. We aimed therefore to investigate the effect of an increased availability of NEFA on gene expression of proteins involved in transmembrane fatty acid (FAT=CD36) and glucose (GLUT4) transport and of the uncoupling proteins UCP2 and 3 at the heart and skeletal muscle level. STUDY DESIGN: Euglycemic hyperinsulinemic clamp was performed after 24 h Intralipid 1 plus heparin or saline infusion in lean Zucker rats. Skeletal and heart muscle glucose utilization was calculated by 2-deoxy-[1-3 H]-D-glucose technique. Quantification of FAT=CD36, GLUT4, UCP2 and UCP3 mRNAs was obtained by Northern blot analysis or RT-PCR. RESULTS: In Intralipid 1 plus heparin infused animals a significant decrease in insulin-mediated glucose uptake was observed both in the heart (22.62 AE 2.04 vs 10.37 AE 2.33 ng=mg=min; P < 0.01) and in soleus muscle (13.46 AE 1.53 vs 6.84 AE 2.58 ng=mg=min; P < 0.05). FAT=CD36 mRNA was significantly increased in skeletal muscle tissue ( þ 117.4 AE 16.3%, P < 0.05), while no differences were found at the heart level in respect to saline infused rats. A clear decrease of GLUT4 mRNA was observed in both tissues. The 24 h infusion of fat emulsion resulted in a clear enhancement of UCP2 and UCP3 mRNA levels in the heart (99.5 AE 15.3 and 80 AE 4%) and in the skeletal muscle (291.5 AE 24.7 and 146.9 AE 12.7%). CONCLUSIONS: As a result of the increased availability of NEFA, FAT=CD36 gene expression increases in skeletal muscle, but not at the heart level. The augmented lipid fuel supply is responsible for the depression of insulin-mediated glucose transport and for the increase of UCP2 and 3 gene expression in both skeletal and heart muscle.

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Section: Nefa and Gene Expression In Rat Heartmentioning

confidence: 99%

Changes in FAT/CD36, UCP2, UCP3 and GLUT4 gene expression during lipid infusion in rat skeletal and heart muscle

et al. 2002

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“…The protonophoric activity of FFA [3,4] is limited by a low £ip-£op ability of FFA anions in arti¢cial [5] and mitochondrial membranes [6]. It has been ¢rst reported by the Skulachev's group [3,7] that carboxyatractyloside, a speci¢c inhibitor of the ADP/ ATP carrier, partially reversed the protonophoric activity of FFA in mitochondria.…”

Section: Introductionmentioning

confidence: 99%

Long‐chain fatty acid‐promoted swelling of mitochondria: further evidence for the protonophoric effect of fatty acids in the inner mitochondrial membrane

2000

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Swelling of non-respiring rat liver mitochondria suspended in isotonic potassium acetate at pH 6.5^7.4 in the presence of valinomycin was promoted by long-chain fatty acids, such as myristate, indicating a protonophoric mechanism. This swelling was partly inhibited by inhibitors or substrates of mitochondrial anion carriers. The results show that the fatty acid cycling mechanism responsible for uncoupling of oxidative phosphorylation can also operate in the direction opposite to that originally proposed [Skulachev, V.P. (1991) FEBS Lett. 294, 158^162], i.e. the inwardly directed transfer of the fatty acid anion accompanied by outwardly directed free passage of undissociated fatty acid. They also extend the list of mitochondrial anion carriers, that are involved in this process, over the mono-and tricarboxylate transporters. At pH 8, myristate, but not the synthetic protonophore, p-trifluoromethoxycarbonylcyanide phenylhydrazone, induced mitochondrial swelling in both potassium acetate and KCl media, that did not require the presence of valinomycin. This indicates that, at alkaline pH, myristate facilitates permeation of the inner mitochondrial membrane to monovalent cations and, possibly, activates the inner membrane anion channel.z 2000 Federation of European Biochemical Societies.

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“…However, a perceived disadvantage of pure fatty acid membranes is that they are highly permeable to protons and are therefore incapable of maintaining pH gradients. Indeed, the addition of a small amount of oleic acid to phospholipid vesicles results in the dissipation of preestablished pH gradients within several seconds (16)(17)(18)(19).…”

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confidence: 99%

Membrane growth can generate a transmembrane pH gradient in fatty acid vesicles

Chen

Szostak²

2004

Proc. Natl. Acad. Sci. U.S.A.

145

140

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Electrochemical proton gradients are the basis of energy transduction in modern cells, and may have played important roles in even the earliest cell-like structures. We have investigated the conditions under which pH gradients are maintained across the membranes of fatty acid vesicles, a model of early cell membranes. We show that pH gradients across such membranes decay rapidly in the presence of alkali-metal cations, but can be maintained in the absence of permeable cations. Under such conditions, when fatty acid vesicles grow through the incorporation of additional fatty acid, a transmembrane pH gradient is spontaneously generated. The formation of this pH gradient captures some of the energy released during membrane growth, but also opposes and limits further membrane area increase. The coupling of membrane growth to energy storage could have provided a growth advantage to early cells, once the membrane composition had evolved to allow the maintenance of stable pH gradients.

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Long-chain fatty acids act as protonophoric uncouplers of oxidative phosphorylation in rat liver mitochondria

Cited by 70 publications

References 32 publications

Changes in FAT/CD36, UCP2, UCP3 and GLUT4 gene expression during lipid infusion in rat skeletal and heart muscle

Changes in FAT/CD36, UCP2, UCP3 and GLUT4 gene expression during lipid infusion in rat skeletal and heart muscle

Long‐chain fatty acid‐promoted swelling of mitochondria: further evidence for the protonophoric effect of fatty acids in the inner mitochondrial membrane

Membrane growth can generate a transmembrane pH gradient in fatty acid vesicles

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