Rebuttal from Manoja K. Brahma, Adam R. Wende and Kyle S. McCommis.
Rebuttal from Manoja K. Brahma, Adam R. Wende and Kyle S. McCommis.
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DOI：
10.1113/jp281453
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
McCommis KS
中科院分区：
文献类型：
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作者：
Brahma MK;Wende AR;McCommis KS
Drs. Karwi and Lopaschuk (2021 JP CrossTalk) have provided compelling evidence of the potential for ketone bodies to provide an extra source of ATP for the heart. The foundation of our opposing views most likely stems from comparing analyses of the acute effects of ketone bodies in predominantly ex vivo studies, to that which occurs in vivo with more chronic ketosis. Likewise, we must all be more prudent when comparing cardiac metabolic adaptations to physiologic ketosis to those observed with “pure” ketosis as occurs with consumption of ketone esters or salts, or ketone infusion. In physiologic states of ketosis such as fasting or consumption of a low-carbohydrate, high-fat ketogenic diet, hearts preferentially downregulate ketolytic enzymes, decreasing ketone oxidation and enhancing fatty acid oxidation (Wentz et al., 2010; McCommis et al., 2020). This downregulation of ketolytic enzymes also occurs in the hearts of diabetic mice, or in hearts overexpressing glucose transporter-4 with enhanced glucose uptake and utilization (Brahma et al., 2020). However, cardiac ketone metabolism may be directly enhanced if delivery of lipids or glucose is not concurrently elevated. Recent studies suggest that ketone ester supplementation enhanced cardiac ketone uptake in humans (Monzo et al., 2020), and ketone ester-enriched diets increased the expression of ketolytic enzymes in the rat heart (Yurista et al., 2020). These studies imply that elevated ketone extraction is associated with increased oxidation, but neither of these studies directly measured oxidation.We agree that ketone utilization appears to be more important in failing hearts. Failing hearts from humans and rodent models display enhanced expression of the ketolytic enzymes β-hydroxybutyrate-dehydrogenase-1 (BDH1) and succinyl-CoA: 3-oxoacid CoA transferase (SCOT) and have been shown to extract more ketones than non-failing hearts (Aubert et al.,
