Regulation of Myocardial Ketone Oxidative Proteins by Increased O ‐GlcNAcylation
In: The FASEB Journal ; volume 30, issue S1 ; ISSN 0892-6638 1530-6860, 2016
academicJournal
Zugriff:
An adult heart exhibits tremendous metabolic flexibility by utilizing a variety of substrates to meet its constant fuel demand. However, this metabolic flexibility is lost during overt diabetes. Moreover, heart mitochondria exhibit a low rate of ketone oxidation in type 1 diabetes. However, the mechanism of this reduction and regulation of the ketolytic pathway in a diabetic heart is incompletely understood. Recently, O ‐linked attachment of N‐acetyl‐glucosamine ( O ‐GlcNAc) to proteins has been recognized as a key glucose‐induced posttranslational modification (PTM) in mediating the adverse effects of diabetes in the cardiovascular system. We therefore sought to test the hypothesis that modulation of transcriptional and/or posttranslational mechanisms via increased protein O ‐GlcNAcylation may induce regulatory changes in the myocardial ketolytic machinery in a diabetic heart. Our findings from the hearts of streptozotocin‐induced diabetic mice confirmed that diabetes promotes significant (P < 0.05) transcriptional suppression of two important ketolytic genes: succinyl‐CoA:3‐oxoacid CoA transferase (SCOT; encoded by Oxct1 ) and 3‐hydroxybutyrate dehydrogenase, type 1 (BDH1; encoded by Bdh1 ). In contrast we found an induction of a ketone synthesis gene, 3‐hydroxy‐3‐methylglutaryl‐Coenzyme A synthase 2 (HMGCS2; encoded by Hmgcs2 ). To dissect out the glucose contribution to the changes seen in the diabetic heart, a transgenic mouse with cardiac‐restricted expression of the glucose transporter 4 (GLUT4; mG4H) was used. Interestingly, mG4H alone was sufficient to reduce cardiac Oxct1 expression of SCOT mRNA and protein levels. This transgene‐specific suppression was maintained even in the diabetic myocardium suggesting that glucose may modulate myocardial ketone body catabolic machinery by multiple mechanisms independent of other changes associated with diabetes. To establish the role of O ‐GlcNAcylation, AC16 human cardiomyocytes were treated with Thiamet G (TMG), an O ‐GlcNAcase (OGA) enzyme inhibitor that ...
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Regulation of Myocardial Ketone Oxidative Proteins by Increased O ‐GlcNAcylation
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Autor/in / Beteiligte Person: | Brahma, Manoja K ; McCrory, Mark A ; Paterson, Andrew J ; Pepin, Mark E ; Young, Martin E ; Wende, Adam R ; National Institutes of Health |
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Zeitschrift: | The FASEB Journal ; volume 30, issue S1 ; ISSN 0892-6638 1530-6860, 2016 |
Veröffentlichung: | Wiley, 2016 |
Medientyp: | academicJournal |
DOI: | 10.1096/fasebj.30.1_supplement.1273.1 |
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