Document Detail

Adaptation of myocardial substrate metabolism to a ketogenic nutrient environment.
MedLine Citation:
PMID:  20529848     Owner:  NLM     Status:  MEDLINE    
Heart muscle is metabolically versatile, converting energy stored in fatty acids, glucose, lactate, amino acids, and ketone bodies. Here, we use mouse models in ketotic nutritional states (24 h of fasting and a very low carbohydrate ketogenic diet) to demonstrate that heart muscle engages a metabolic response that limits ketone body utilization. Pathway reconstruction from microarray data sets, gene expression analysis, protein immunoblotting, and immunohistochemical analysis of myocardial tissue from nutritionally modified mouse models reveal that ketotic states promote transcriptional suppression of the key ketolytic enzyme, succinyl-CoA:3-oxoacid CoA transferase (SCOT; encoded by Oxct1), as well as peroxisome proliferator-activated receptor alpha-dependent induction of the key ketogenic enzyme HMGCS2. Consistent with reduction of SCOT, NMR profiling demonstrates that maintenance on a ketogenic diet causes a 25% reduction of myocardial (13)C enrichment of glutamate when (13)C-labeled ketone bodies are delivered in vivo or ex vivo, indicating reduced procession of ketones through oxidative metabolism. Accordingly, unmetabolized substrate concentrations are higher within the hearts of ketogenic diet-fed mice challenged with ketones compared with those of chow-fed controls. Furthermore, reduced ketone body oxidation correlates with failure of ketone bodies to inhibit fatty acid oxidation. These results indicate that ketotic nutrient environments engage mechanisms that curtail ketolytic capacity, controlling the utilization of ketone bodies in ketotic states.
Anna E Wentz; D André d'Avignon; Mary L Weber; David G Cotter; Jason M Doherty; Robnet Kerns; Rakesh Nagarajan; Naveen Reddy; Nandakumar Sambandam; Peter A Crawford
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-06-07
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-08-02     Completed Date:  2010-09-20     Revised Date:  2013-05-29    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  24447-56     Citation Subset:  IM    
Department of Medicine, Washington University, St Louis, Missouri 63108, USA.
Data Bank Information
Bank Name/Acc. No.:
GEO/GSE14929;  GSE21368
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MeSH Terms
Carbon Isotopes / chemistry
Coenzyme A-Transferases / metabolism
Immunohistochemistry / methods
Ketone Bodies / chemistry
Ketones / chemistry
Mice, Inbred C57BL
Mice, Transgenic
Models, Biological
Myocardium / metabolism*
Myocytes, Cardiac / cytology
Peroxisome Proliferator-Activated Receptors / metabolism
Grant Support
Reg. No./Substance:
0/Carbon Isotopes; 0/Ketone Bodies; 0/Ketones; 0/Peroxisome Proliferator-Activated Receptors; EC 2.8.3.-/Coenzyme A-Transferases; EC CoA-transferase

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