TY - JOUR
T1 - Adaptation of myocardial substrate metabolism to a ketogenic nutrient environment
AU - Wentz, Anna E.
AU - D'Avignon, D. André
AU - Weber, Mary L.
AU - Cotter, David G.
AU - Doherty, Jason M.
AU - Kerns, Robnet
AU - Nagarajan, Rakesh
AU - Reddy, Naveen
AU - Sambandam, Nandakumar
AU - Crawford, Peter A.
PY - 2010/8/6
Y1 - 2010/8/6
N2 - 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 α-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 13C enrichment of glutamate when 13C-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.
AB - 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 α-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 13C enrichment of glutamate when 13C-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.
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U2 - 10.1074/jbc.M110.100651
DO - 10.1074/jbc.M110.100651
M3 - Article
C2 - 20529848
AN - SCOPUS:77955301740
SN - 0021-9258
VL - 285
SP - 24447
EP - 24456
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 32
ER -