Effect of fatty acids on energy coupling processes in mitochondria

Wojtczak, Lech; Schönfeld, Peter

doi:10.1016/0005-2728(93)90004-y

Cited by 331 publications

(191 citation statements)

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“…One of these could be the uncoupling of oxidative phosphorylation, a phenomenon that has been observed in isolated rat adipocytes stimulated with lipolytic hormones (50,56) and is in keeping with the intrinsic uncoupling effects of FFAs on mitochondria (60). Another is the energy consumed by the formation of glycerol 3-phosphate used for reesterification of FFAs.…”

Section: Discussionmentioning

confidence: 91%

AMP-activated Protein Kinase Is Activated as a Consequence of Lipolysis in the Adipocyte

Gauthier

Miyoshi

Souza

et al. 2008

Journal of Biological Chemistry

225

207

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AMP-activated protein kinase (AMPK) is activated in adipocytes during exercise and other states in which lipolysis is stimulated. However, the mechanism(s) responsible for this effect and its physiological relevance are unclear. To examine these questions, 3T3-L1 adipocytes were treated with cAMP-inducing agents (isoproterenol, forskolin, and isobutylmethylxanthine), which stimulate lipolysis and activate AMPK. When lipolysis was partially inhibited with the general lipase inhibitor orlistat, AMPK activation by these agents was also partially reduced, but the increases in cAMP levels and cAMP-dependent protein kinase (PKA) activity were unaffected. Likewise, small hairpin RNA-mediated silencing of adipose tissue triglyceride lipase inhibited both forskolin-stimulated lipolysis and AMPK activation but not that of PKA. Forskolin treatment increased the AMP:ATP ratio, and this too was reduced by orlistat. When acyl-CoA synthetase, which catalyzes the conversion of fatty acids to fatty acyl-CoA, was inhibited with triacsin C, the increases in both AMPK activity and AMP:ATP ratio were blunted. Isoproterenol-stimulated lipolysis was accompanied by an increase in oxidative stress, an effect that was quintupled in cells incubated with the AMPK inhibitor compound C. The isoproterenol-induced increase in the AMP:ATP ratio was also much greater in these cells. In conclusion, the results indicate that activation of AMPK in adipocytes by cAMP-inducing agents is a consequence of lipolysis and not of PKA activation. They suggest that AMPK activation in this setting is caused by an increase in the AMP:ATP ratio that appears to be due, at least in part, to the acylation of fatty acids. Finally, this AMPK activation appears to restrain the energy depletion and oxidative stress caused by lipolysis. AMP-activated protein kinase (AMPK)2 is a sensor of cellular energy state that responds to metabolic stresses and other regulatory signals. The mechanism of activation of AMPK is a complex phenomenon and is still not fully understood, although it is recognized that it involves phosphorylation of the critical Thr-172 residue of its ␣ catalytic subunit by upstream kinases such as LKB1, Ca 2ϩ -calmodulin-dependent protein kinase kinase, and possibly Tak1, a member of the mitogenactivated protein kinase kinase kinase family (1-5). AMPK is also regulated by AMP allosterically and the current view is that this both increases AMPK activity directly and makes it a poorer substrate for phosphatases (6).The role and regulation of AMPK in muscle, liver, and various cultured cells have been extensively studied. It is now well established that energy depletion because of starvation, hypoxia, and exercise increases the intracellular AMP:ATP ratio and secondarily AMPK activity (7). Upon its activation, a major role of AMPK is to replete cellular energy stores by stimulating processes that generate ATP, such as fatty acid oxidation, and inhibiting ATP-consuming pathways (e.g. lipogenesis, triglyceride synthesis, and gluconeogenesis) that are not acutel...

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Section: Discussionmentioning

confidence: 91%

AMP-activated Protein Kinase Is Activated as a Consequence of Lipolysis in the Adipocyte

Gauthier

Miyoshi

Souza

et al. 2008

Journal of Biological Chemistry

225

207

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“…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. In this respect the observation of a clear enhancement of both UCP2 and 3 gene expression either in the heart and in skeletal muscle, following the 24 h infusion of fat emulsion, is noteworthy, but at present we do not possess a definitive explanation of the phenomenon.…”

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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“…Transmembranal proteins, such as the ADP/ATP carrier, the aspartate/glutamate carrier, the dicarboxylate carrier and the uncoupling protein, are involved in the protonophoric activity of FFA in a tissue-dependent manner (for review, see [16,17]). The protonophoric activity of phytanic acid is comparable to that of the unbranched analogue palmitic acid, but its sensitivity to e¡ectors of the ADP/ ATP carrier or the aspartate/glutamate carrier is much weaker in liver mitochondria.…”

Section: Discussionmentioning

confidence: 99%

Refsum disease diagnostic marker phytanic acid alters the physical state of membrane proteins of liver mitochondria

Schönfeld

Struy

1999

FEBS Letters

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Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid), a branched chain fatty acid accumulating in Refsum disease to high levels throughout the body, induces uncoupling of rat liver mitochondria similar to non-branched fatty acids (e.g. palmitic acid), but the contribution of the ADP/ATP carrier or the aspartate/glutamate carrier in phytanic acid-induced uncoupling is of minor importance. Possible deleterious effects of phytanic acid on membrane-linked energy coupling processes were studied by ESR spectroscopy using rat liver mitochondria and a membrane preparation labeled with the lipid-specific spin probe 5-doxylstearic acid (5-DSA) or the protein-specific spin probe MAL-TEMPO (4-maleimido-2,2,6,6-tetramethyl-piperidine-1-oxyl). The effects of phytanic acid on phospholipid molecular dynamics and on the physical state of membrane proteins were quantified by estimation of the order parameter or the ratio of the amplitudes of the weakly to strongly immobilized MAL-TEMPO binding sites (W/S ratio), respectively. It was found, that phytanic acid (1) increased the mobility of phospholipid molecules (indicated by a decrease in the order parameter) and (2) altered the conformational state and/or the segmental mobility of membrane proteins (indicated by a drastic decrease in the W/S ratio). Unsaturated fatty acids with multiple cis-double bonds (e.g. linolenic or arachidonic acid), but not nonbranched FFA (ranging from chain length C10:0 to C18:0), also decrease the W/S ratio. It is hypothesized that the interaction of phytanic acid with transmembrane proteins might stimulate the proton permeability through the mitochondrial inner membrane according to a mechanism, different to a protein-supported fatty acid cycling.z 1999 Federation of European Biochemical Societies.

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Effect of fatty acids on energy coupling processes in mitochondria

Cited by 331 publications

References 181 publications

AMP-activated Protein Kinase Is Activated as a Consequence of Lipolysis in the Adipocyte

AMP-activated Protein Kinase Is Activated as a Consequence of Lipolysis in the Adipocyte

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

Refsum disease diagnostic marker phytanic acid alters the physical state of membrane proteins of liver mitochondria

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