Adaptation of Myocardial Substrate Metabolism to a Ketogenic Nutrient Environment

Abstract

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 proliferatoractivated receptor ␣-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.The mammalian heart must maintain constant levels of ATP to perform its mechanical and electrical functions. A variety of experimental approaches have established that cardiomyopathy is associated with changes in cardiac energy metabolism and that altered energy metabolism can cause cardiomyopathy (1-5). In the normal adult heart, mitochondrial oxidative phosphorylation provides more than 95% of the ATP generated. Substrate utilization is dynamic, and metabolic flexibility under differing physiological conditions is an important adaptive property of myocardium (6 -8). Adaptations over time are

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

“…Serum and blood metabolic parameters were measured in samples collected following a 4-hour fast, as described previously (31).…”

Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet

“…Blood and resulting serum samples were acquired from animals that had been fasted for 5 h and maintained on fresh cedar chip bedding and were collected midmorning. Serum metabolites and insulin were measured as previously described (62). Hepatic triglycerides (TG), using a Folch extract of liver and biochemical quantification, were quantified as previously described (14).…”

“…Quantification of gene expression was performed using real-time RT-qPCR using the ⌬⌬Ct approach as described, normalizing to Rpl32, using primer sequences listed within Supplemental Table S1 (supplemental material for this article is available online at the American Journal of Physiology Gastrointestinal and Liver Physiology website) (62). All RT-qPCR reactions used the ThermoFisher Abgene 2X Sybr green reagent with 900 nM each primer, with the exception of X-box binding protein 1 (XBP1) Xbp1-S primers, which also included 20 mM NH 4SO4 and 3 M each primer.…”

“…Nonetheless, the full scope of metabolic effects incurred by low-, and very low (ketogenic)-carbohydrate diets (KD) has only been preliminarily characterized. In wild-type mice, KDs result in weight loss and increased hepatic and myocardial fatty acid oxidation, compared with mice maintained on standard chow diets rich in polysaccharides (5,35,62). Whereas leptin-deficient obese (ob/ob) animals maintained on KD for 7 wk exhibit persistent weight gain, glucose tolerance and insulin resistance improve compared with ob/ob mice maintained on standard chow diet (3, 57).…”

A 1-week extension of a ketogenic diet provides a further decrease in myocardial 18F-FDG uptake and a high detectability of myocarditis with FDG-PET

“…Such diet can be prescribed at a much longer term than fasting, [13][14][15] leading to metabolic changes that are known to progressively suppress the metabolic use of glucose, even in the brain, within at least a 3-to 5-day period. [15][16][17][18] …”