A Novel Inhibitor of Pyruvate Dehydrogenase Kinase Stimulates Myocardial Carbohydrate Oxidation in Diet-Induced Obesity

dc.contributor.authorWu, C. -Y
dc.contributor.authorSatapati, S.
dc.contributor.authorGui, W.
dc.contributor.authorMax Wynn, R.
dc.contributor.authorSharma, G.
dc.contributor.authorLou, M.
dc.contributor.authorQi, X.
dc.contributor.authorBurgess, S. C.
dc.contributor.authorMalloy, C.
dc.contributor.authorKhemtong, C.
dc.contributor.authorSherry, A. Dean
dc.contributor.authorChuang, D. T.
dc.contributor.authorMerritt, M. E.
dc.contributor.utdAuthorSherry, A. Dean
dc.date.accessioned2019-05-31T20:11:13Z
dc.date.available2019-05-31T20:11:13Z
dc.date.created2018-05-08
dc.descriptionIncludes supplementary material
dc.description.abstractThe pyruvate dehydrogenase complex (PDC) is a key control point of energy metabolism and is subject to regulation by multiple mechanisms, including posttranslational phosphorylation by pyruvate dehydrogenase kinase (PDK). Pharmacological modulation of PDC activity could provide a new treatment for diabetic cardiomyopathy, as dysregulated substrate selection is concomitant with decreased heart function. Dichloroacetate (DCA), a classic PDK inhibitor, has been used to treat diabetic cardiomyopathy, but the lack of specificity and side effects of DCA indicate a more specific inhibitor of PDK is needed. This study was designed to determine the effects of a novel and highly selective PDK inhibitor, 2((2,4-dihydroxyphenyl)sulfonyl) isoindoline-4,6-diol (designated PS10), on pyruvate oxidation in diet-induced obese (DIO) mouse hearts compared with DCA-treated hearts. Four groups of mice were studied: lean control, DIO, DIO + DCA, and DIO + PS10. Both DCA and PS10 improved glucose tolerance in the intact animal. Pyruvate metabolism was studied in perfused hearts supplied with physiological mixtures of long chain fatty acids, lactate, and pyruvate. Analysis was performed using conventional ¹H and ¹³C isotopomer methods in combination with hyperpolarized [1-¹³C]pyruvate in the same hearts. PS10 and DCA both stimulated flux through PDC as measured by the appearance of hyperpolarized [¹³C]bicarbonate. DCA but not PS10 increased hyperpolarized [1-¹³C]lactate production. Total carbohydrate oxidation was reduced in DIO mouse hearts but increased by DCA and PS10, the latter doing so without increasing lactate production. The present results suggest that PS10 is a more suitable PDK inhibitor for treatment of diabetic cardiomyopathy.
dc.description.departmentSchool of Natural Sciences and Mathematics
dc.description.sponsorshipThis work was supported by National Institutes of Health Grants DK62306, R37-HL034557, and P41-EB015908 and by Welch Foundation Grants I-1286 and I-1804. This work was also supported by National Institutes of Health Grants R01s DK105346, HD087306, DK112865, P41122698, and U24DK097209 and by NSF DMR 1644779.
dc.identifier.bibliographicCitationWu, C. -Y, S. Satapati, W. Gui, R. Max Wynn, et al. 2018. "A novel inhibitor of pyruvate dehydrogenase kinase stimulates myocardial carbohydrate oxidation in diet-induced obesity." Journal of Biological Chemistry 293(25): 9604-9613, doi:10.1074/jbc.RA118.002838
dc.identifier.issn0021-9258
dc.identifier.issue25
dc.identifier.urihttps://hdl.handle.net/10735.1/6524
dc.identifier.volume293
dc.language.isoen
dc.publisherAmerican Society for Biochemistry and Molecular Biology Inc.
dc.relation.urihttp://dx.doi.org/10.1074/jbc.RA118.002838
dc.rightsPublished under exclusive license
dc.rights©2018 The Authors
dc.source.journalJournal of Biological Chemistry
dc.subjectCardiomyopathies
dc.subjectMagnetic Resonance Imaging
dc.subjectDiabetes Mellitus
dc.subjectGlucose Metabolism Disorders
dc.subjectMetabolism
dc.subjectFatty acids
dc.subjectMitochondria
dc.titleA Novel Inhibitor of Pyruvate Dehydrogenase Kinase Stimulates Myocardial Carbohydrate Oxidation in Diet-Induced Obesity
dc.type.genrearticle

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