Phosphorylation of cardiac protein kinase B is regulated by palmitate

Soltys, Carrie-Lynn M.; Buchholz, Lori; Gandhi, Manoj; Clanachan, Alexander S.; Walsh, Kenneth; Dyck, Jason R.B.

doi:10.1152/ajpheart.00275.2002

Cited by 48 publications

(55 citation statements)

References 43 publications

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“…We examined through which of the postreceptor signaling pathways insulin provoked an increase in total FAT/ CD36 content. As has been shown previously (26,29), exposure (5 min) of cardiac myocytes to insulin increased the phosphorylation of Akt (Ser 473 and Thr 308 ), ERK1/2, and PKC / , and these insulin-induced phosphorylations were blocked by LY-29004, UO-126, and PKC-ps, respectively (data not shown). Blocking of the PKC / -signaling pathway did not inhibit the insulin-induced expression of FAT/CD36 (P Ͼ 0.05; Fig.…”

Section: Effects Of Insulin On Subcellular Distribution Of Fat/cd36 Asupporting

confidence: 82%

“…Recent studies have provided evidence that different signaling pathways can contribute to protein synthesis in cardiac myocytes (15,32), and insulin can activate a number of signaling pathways (26,29). Blocking insulin signaling through the MAP kinase-and PKC / -signaling pathways failed to inhibit the insulin-induced increase in FAT/CD36 Fig.…”

Section: Fig 4 Effects Of Insulin On Fat/cd36 (A)mentioning

confidence: 98%

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Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm

Chabowski

Coort²,

Callés-Escandon³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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Because insulin has been shown to stimulate long-chain fatty acid (LCFA) esterification in skeletal muscle and cardiac myocytes, we investigated whether insulin increased the rate of LCFA transport by altering the expression and the subcellular distribution of the fatty acid transporters FAT/CD36 and FABPpm. In cardiac myocytes, insulin very rapidly increased the expression of FAT/CD36 protein in a time-and dose-dependent manner. During a 2-h period, insulin (10 nM) increased cardiac myocyte FAT/CD36 protein by 25% after 60 min and attained a maximum after 90 -120 min (ϩ40 -50%). There was a dose-dependent relationship between insulin (10 Ϫ12 to 10 Ϫ7 M) and FAT/CD36 expression. The half-maximal increase in FAT/CD36 protein occurred at 0.5 ϫ 10 Ϫ9 M insulin, and the maximal increase occurred at 10 Ϫ9 to 10 Ϫ8 M insulin (ϩ40 -50%). There were similar insulin-induced increments in FAT/CD36 protein in cardiac myocytes (ϩ43%) and in Langendorff-perfused hearts (ϩ32%). In contrast to FAT/CD36, insulin did not alter the expression of FABPpm protein in either cardiac myocytes or the perfused heart. By use of specific inhibitors of insulin-signaling pathways, it was shown that insulin-induced expression of FAT/CD36 occurred via the PI 3-kinase/Akt insulin-signaling pathway. Subcellular fractionation of cardiac myocytes revealed that insulin not only increased the expression of FAT/CD36, but this hormone also targeted some of the FAT/CD36 to the plasma membrane while concomitantly lowering the intracellular depot of FAT/ CD36. At the functional level, the insulin-induced increase in FAT/ CD36 protein resulted in an increased rate of palmitate transport into giant vesicles (ϩ34%), which paralleled the increase in plasmalemmal FAT/CD36 (ϩ29%). The present studies have shown that insulin regulates protein expression of FAT/CD36, but not FABPpm, via the PI 3-kinase/Akt insulin-signaling pathway. fatty acid translocase; plasma membrane-associated fatty acid-binding protein; cardiac myocytes; transport; plasma membrane; low-density microsomes; perfusion; heart LONG-CHAIN FATTY ACIDS (LCFAs) are taken up into cells by passive diffusion and by protein-mediated mechanisms involving a number of fatty acid-binding proteins (12,25). Overexpression of fatty acid transporters, including fatty acid translocase (FAT/CD36) and plasma membrane-associated fatty acid-binding protein (FABPpm), increase LCFA uptake (13,14). In recent years, it has been shown that rates of LCFA transport can be regulated acutely and chronically. In heart and skeletal muscle exposed briefly to insulin (15 min) and in contracting muscle (Ͻ30 min), rates of LCFA transport are increased due to the translocation of FAT/CD36 from an intracellular depot to the plasma membrane (4, 18, 19). Expression of FAT/CD36 mRNA is upregulated by LCFAs in neonatal cardiac myocytes (30), although the functional metabolic consequences of these changes on LCFA transport and metabolism have not been determined. In more detailed studies, FAT/CD36 mRNA and protein expression and plasma...

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Section: Effects Of Insulin On Subcellular Distribution Of Fat/cd36 Asupporting

confidence: 82%

Section: Fig 4 Effects Of Insulin On Fat/cd36 (A)mentioning

confidence: 98%

Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm

Chabowski

Coort²,

Callés-Escandon³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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“…However, insulin did not appear to be present in the perfusate in the study of Irie et al, 21 which may have inhibited glucose uptake. 27 In addition, because the concentration of insulin used in our study was supraphysiological, it is possible that this high concentration of insulin may have beneficial effects on function by itself. 28 The presence of insulin in the perfusate may have increased cardiac glucose utilization, which could play a role in the improved performance observed in the FAT/CD36-KO hearts in the present study.…”

Section: Discussionmentioning

confidence: 97%

Fatty Acid Translocase/CD36 Deficiency Does Not Energetically or Functionally Compromise Hearts Before or After Ischemia

et al. 2004

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Background-Evidence from humans suggests that fatty acid translocase (FAT)/CD36 deficiency can lead to functionally and/or energetically compromised hearts, but the data are equivocal, and the subject remains controversial. In this report we assessed the contribution of FAT/CD36 to overall fatty acid oxidation rates in the intact heart and determined the effect of FAT/CD36 on energy metabolism during reperfusion of ischemic hearts. Methods and Results-Isolated working hearts from wild-type and FAT/CD36-knockout (KO) mice were perfused with Krebs-Henseleit solution containing 0..5 mmol/L calcium, and 100 U/mL insulin at a preload pressure of 11.5 mm Hg and afterload pressure of 50 mm Hg. Hearts were aerobically perfused for 30 minutes or aerobically perfused for 30 minutes, followed by 18 minutes of global no-flow ischemia and 40 minutes of aerobic reperfusion. Rates of fatty acid oxidation in FAT/CD36-KO hearts were significantly lower than in wild-type hearts at both concentrations of palmitate (0.4 or 1.2 mmol/L). In addition, hearts from FAT/CD36-KO mice displayed a compensatory increase in glucose oxidation rates. On aerobic reperfusion after ischemia, cardiac work of FAT/CD36-KO hearts recovered to the same extent as wild-type hearts. Conclusions-FAT/CD36-deficient

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“…The unsaturated FFA oleate increased PI3K activity, whereas the saturated FFA palmitate decreased it. Others have reported that the activity of Akt/PKB, the downstream target of PI3K, was reduced by palmitate treatment (54,55). Because downstream targets of the PI3K/Akt signaling pathway that have been identified include the inhibition of proapoptotic proteins Bad and Bax (56, 57), we initially hypothesized that palmitateinduced apoptosis might involve an activation of the proapoptotic Bcl-2 family proteins, resulting from the inactivation of the PI3K/Akt pathway.…”

Section: Discussionmentioning

confidence: 99%

Saturated Fatty Acid-induced Apoptosis in MDA-MB-231 Breast Cancer Cells

Hardy

El-Assaad

Przybytkowski

et al. 2003

Journal of Biological Chemistry

247

243

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Little is known about the biochemical basis of the action of free fatty acids (FFA) on breast cancer cell proliferation and apoptosis. Here we report that unsaturated FFAs stimulated the proliferation of human MDA-MB-231 breast cancer cells, whereas saturated FFAs inhibited it and caused apoptosis. Saturated FFA palmitate decreased the mitochondrial membrane potential and caused cytochrome c release. Palmitate-induced apoptosis was enhanced by the fat oxidation inhibitor etomoxir, whereas it was reduced by fatty-acyl CoA synthase inhibitor triacsin C. The non-metabolizable analog 2-bromopalmitate was not cytotoxic. This indicates that palmitate must be metabolized to exert its toxic effect but that its action does not involve fat oxidation. Pharmacological studies showed that the action of palmitate is not mediated via ceramides, reactive oxygen species, or changes in phosphatidylinositol 3-kinase activity. Palmitate caused early enhancement of cardiolipin turnover and decreased the levels of this mitochondrial phospholipid, which is necessary for cytochrome c retention. Cosupplementation of oleate, or increasing ␤-oxidation with the AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-␤-D-ribonucleoside, both restored cardiolipin levels and blocked palmitate-induced apoptosis. Oleate was preferentially metabolized to triglycerides, and oleate cosupplementation channeled palmitate esterification processes to triglycerides. Overexpression of Bcl-2 family members blocked palmitateinduced apoptosis. The results provide evidence that a decrease in cardiolipin levels and altered mitochondrial function are involved in palmitate-induced breast cancer cell death. They also suggest that the antiapoptotic action of oleate on palmitate-induced cell death involves both restoration of cardiolipin levels and redirection of palmitate esterification processes to triglycerides.

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Phosphorylation of cardiac protein kinase B is regulated by palmitate

Cited by 48 publications

References 43 publications

Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm

Insulin stimulates fatty acid transport by regulating expression of FAT/CD36 but not FABPpm

Fatty Acid Translocase/CD36 Deficiency Does Not Energetically or Functionally Compromise Hearts Before or After Ischemia

Saturated Fatty Acid-induced Apoptosis in MDA-MB-231 Breast Cancer Cells

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