Adaptation of myocardial substrate metabolism to a ketogenic nutrient environment.
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.
Department of Medicine, Washington University, St Louis, Missouri 63108, USA.
Anna E
AE
Wentz
D André
DA
d'Avignon
Mary L
ML
Weber
David G
DG
Cotter
Jason M
JM
Doherty
Robnet
R
Kerns
Rakesh
R
Nagarajan
Naveen
N
Reddy
Nandakumar
N
Sambandam
Peter A
PA
Crawford
D000818:Animals; D002247:Carbon Isotopes / Q000737:chemistry; D015256:Coenzyme A-Transferases / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D007657:Ketone Bodies / Q000737:chemistry; D007659:Ketones / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D051381:Rats
D002247:Carbon Isotopes; D007657:Ketone Bodies; D007659:Ketones; D047492:Peroxisome Proliferator-Activated Receptors; D015256:Coenzyme A-Transferases; C021460:3-ketoacid CoA-transferase