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Am J Physiol Heart Circ Physiol. 2017 Sep 1;313(3):H479-H490. doi: 10.1152/ajpheart.00191.2017. Epub 2017 Jul 7.

FoxO1 regulates myocardial glucose oxidation rates via transcriptional control of pyruvate dehydrogenase kinase 4 expression.

Gopal K1,2,3, Saleme B4,3, Al Batran R1,2,3, Aburasayn H1,2,3, Eshreif A1,2,3, Ho KL1,5,2,3, Ma WK1, Almutairi M1,2,3, Eaton F1,2,3, Gandhi M1,2,3, Park EA6,7, Sutendra G4,3, Ussher JR8,2,3.

Author information

1
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
2
Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
3
Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
4
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
5
Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada.
6
Department of Pharmacology, University of Tennessee Health Science Center, Memphis, Tennessee; and.
7
Department of Veterans Affairs Medical Center, Memphis, Tennessee.
8
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada; jussher@ualberta.ca.

Abstract

Pyruvate dehydrogenase (PDH) is the rate-limiting enzyme for glucose oxidation and a critical regulator of metabolic flexibility during the fasting to feeding transition. PDH is regulated via both PDH kinases (PDHK) and PDH phosphatases, which phosphorylate/inactivate and dephosphorylate/activate PDH, respectively. Our goal was to determine whether the transcription factor forkhead box O1 (FoxO1) regulates PDH activity and glucose oxidation in the heart via increasing the expression of Pdk4, the gene encoding PDHK4. To address this question, we differentiated H9c2 myoblasts into cardiac myocytes and modulated FoxO1 activity, after which Pdk4/PDHK4 expression and PDH phosphorylation/activity were assessed. We assessed binding of FoxO1 to the Pdk4 promoter in cardiac myocytes in conjunction with measuring the role of FoxO1 on glucose oxidation in the isolated working heart. Both pharmacological (1 µM AS1842856) and genetic (siRNA mediated) inhibition of FoxO1 decreased Pdk4/PDHK4 expression and subsequent PDH phosphorylation in H9c2 cardiac myocytes, whereas 10 µM dexamethasone-induced Pdk4/PDHK4 expression was abolished via pretreatment with 1 µM AS1842856. Furthermore, transfection of H9c2 cardiac myocytes with a vector expressing FoxO1 increased luciferase activity driven by a Pdk4 promoter construct containing the FoxO1 DNA-binding element region, but not in a Pdk4 promoter construct lacking this region. Finally, AS1842856 treatment in fasted mice enhanced glucose oxidation rates during aerobic isolated working heart perfusions. Taken together, FoxO1 directly regulates Pdk4 transcription in the heart, thereby controlling PDH activity and subsequent glucose oxidation rates.NEW & NOTEWORTHY Although studies have shown an association between FoxO1 activity and pyruvate dehydrogenase kinase 4 expression, our study demonstrated that pyruvate dehydrogenase kinase 4 is a direct transcriptional target of FoxO1 (but not FoxO3/FoxO4) in the heart. Furthermore, we report here, for the first time, that FoxO1 inhibition increases glucose oxidation in the isolated working mouse heart.

KEYWORDS:

forkhead box protein O1; glucose oxidation; heart; pyruvate dehydrogenase; pyruvate dehydrogenase kinase

PMID:
28687587
DOI:
10.1152/ajpheart.00191.2017
[Indexed for MEDLINE]
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