Ketone Body Metabolism in the Ischemic Heart

Ketone bodies have been identified as an important, alternative fuel source in heart failure. In addition, the use of ketone bodies as a fuel source has been suggested to be a potential ergogenic aid for endurance exercise performance. These findings have certainly renewed interest in the use of ketogenic diets and exogenous supplementation in an effort to improve overall health and disease. However, given the prevalence of ischemic heart disease and myocardial infarctions, these strategies may not be ideal for individuals with coronary artery disease. Although research studies have clearly defined changes in fatty acid and glucose metabolism during ischemia and reperfusion, the role of ketone body metabolism in the ischemic and reperfused myocardium is less clear. This review will provide an overview of ketone body metabolism, including the induction of ketosis via physiological or nutritional strategies. In addition, the contribution of ketone body metabolism in healthy and diseased states, with a particular emphasis on ischemia-reperfusion (I-R) injury will be discussed.

Why the diabetic heart is energy inefficient: A ketogenesis and ketolysis perspective

Lack of glucose uptake compromises metabolic flexibility and reduces energy efficiency in the diabetes mellitus (DM) heart. Although increased utilization of fatty acid to compensate glucose substrate has been studied, less is known about ketone body metabolism in the DM heart. Ketogenic diet reduces obesity, a risk factor for T2DM. How ketogenic diet affects ketone metabolism in the DM heart remains unclear. At the metabolic level, the DM heart differs from the non-DM heart due to altered metabolic substrate and the T1DM heart differs from the T2DM heart due to insulin levels. How these changes affect ketone body metabolism in the DM heart are poorly understood. Ketogenesis produces ketone bodies by utilizing acetyl CoA whereas ketolysis consumes ketone bodies to produce acetyl CoA, showing their opposite roles in the ketone body metabolism. Cardiac-specific transgenic upregulation of ketogenesis enzyme or knockout of ketolysis enzyme causes metabolic abnormalities leading to cardiac dysfunction. Empirical evidence demonstrates upregulated transcription of ketogenesis enzymes, no change in the levels of ketone body transporters, very high levels of ketone bodies, and reduced expression and activity of ketolysis enzymes in the T1DM heart. Based on these observations, I hypothesize that increased transcription and activity of cardiac ketogenesis enzyme suppresses ketolysis enzymes in the DM heart, which decreases cardiac energy efficiency. The T1DM heart exhibits highly upregulated ketogenesis compared to T2DM due to lack of insulin that inhibits ketogenesis enzyme.

Differential Response of Hippocampal and Cerebrocortical Autophagy and Ketone Body Metabolism to the Ketogenic Diet

Experimental and clinical data support the neuroprotective properties of the ketogenic diet and ketone bodies, but there is still a lot to discover to comprehensively understand the underlying mechanisms. Autophagy is a key mechanism for maintaining cell homeostasis, and therefore its proper function is necessary for preventing accelerated brain aging and neurodegeneration. Due to many potential interconnections, it is possible that the stimulation of autophagy may be one of the mediators of the neuroprotection afforded by the ketogenic diet. Recent studies point to possible interconnections between ketone body metabolism and autophagy. It has been shown that autophagy is essential for hepatic and renal ketogenesis in starvation. On the other hand, exogenous ketone bodies modulate autophagy both in vitro and in vivo. Many regional differences occur between brain structures which concern i.e., metabolic responses and autophagy dynamics. The aim of the present study was to evaluate the influence of the ketogenic diet on autophagic markers and the ketone body utilizing and transporting proteins in the hippocampus and frontal cortex. C57BL/6N male mice were fed with two ketogenic chows composed of fat of either animal or plant origins for 4 weeks. Markers of autophagosome formation as well as proteins associated with ketolysis (BDH1—3-hydroxybutyrate dehydrogenase 1, SCOT/OXCT1—succinyl CoA:3-oxoacid CoA transferase), ketone transport (MCT1—monocarboxylate transporter 1) and ketogenesis (HMGCL, HMGCS2) were measured. The hippocampus showed a robust response to nutritional ketosis in both changes in the markers of autophagy as well as the levels of ketone body utilizing and transporting proteins, which was also accompanied by increased concentrations of ketone bodies in this brain structure, while subtle changes were observed in the frontal cortex. The magnitude of the effects was dependent on the type of ketogenic diet used, suggesting that plant fats may exert a more profound effect on the orchestrated upregulation of autophagy and ketone body metabolism markers. The study provides a foundation for a deeper understanding of the possible interconnections between autophagy and the neuroprotective efficacy of nutritional ketosis.

The metabolic effects of multi-trace elements on parenteral nutrition for pediatric patients: A Randomized Control Trial and Metabolomic Research

Objectives: The recommended dose of multi-trace element injection Ⅰ (MTEI-(Ⅰ)), and the effects of MTEI-(Ⅰ) on nutrient metabolism were investigated by supplementing different doses of multi-trace element parenteral nutrition (PN) to severe pediatric subjects. Methods: Enrolled subjects were randomly divided into two groups: Group A (low-dose group) received MTEI-(I) at 1 mL/kg/d, and Group B (high-dose group) received MTEI-(I) at 2 mL/kg/d, with a maximum dose of 15 mL/d. Patient blood samples before PN, and five day after treatment were collected for trace element detection and metabolomics analyses. Results: After 5 days treatment, white blood counts (WBC), nitrogen (N), chromium (Cr), total bilirubin (TB), direct bilirubin (DB) and albumin (ALB) levels in both groups were variably decreased; of which, WBC (p=0.011) and Cr (p=0.007) levels of subjects in Group B were significantly decreased; Overall, after 5 days of treatment, manganese (Mn) and copper (Cu) levels were decreased, zinc (Zn) and selenium (Se) levels were increased. The increase of Zn (A: 0.170±0.479 VS B：0.193±0.900)and decrease of Cu (A: -0.240±0.382 VS B: -0.373±0.465) of subjects in group B were particularly greater than those in group A. After 5 days treatment, valine, leucine, isoleucine degradation (α-ketoisovaleric acid) products, taurine and hypotaurine metabolism (hypotaurine), arginine and proline metabolism (phosphocreatine), ketone body metabolism (acetoacetic acid and acetone), and other metabolic outputs were decreased (p＜0.05). For Group B, β-oxidation of very long chain fatty acids (hexacosanoic acid), arginine and proline metabolism (phosphocreatine), pentose phosphate metabolism (D-ribose), ketone body metabolism (acetone), citric acid cycle (succinic acid), purine metabolism (adenine), caffeine metabolism (dimethylxanthine) and pyruvate metabolism (acetyl phosphate) were variably decreased (p＜0.05) when compared with Group A at T5. Conclusions: Our work suggested that the high-dose administration of MTEI-(I) is safe for severe pediatric patients. It may alleviate inflammation and antioxidation, relieved hyper caused by stress, improved tissues-based hypoxia, and improved renal function. (Trial registration: ChiCTR-IPR-17013037. Registered 19 October 2017, http://www.chictr.org.cn/showproj.aspx?proj=22327)

Epigenetic Inactivation of Acetyl-Co A acetyltransferase 1 promotes the proliferation and metastasis of nasopharyngeal carcinoma via decreasing ketogenesis

Background Acy1 Coenzyme A Acyltransferases1 (ACAT1) is a key enzyme in the metabolism of ketone bodies, but its expression and biological function in the pathogenesis of NPC remains underexplored. Methods The mRNA and protein expression levels of ACAT1 in NPC and normal control tissues were analyzed by qPCR and immunohistochemistry staining, respectively. GEO database was applied for meta-analysis of ACAT1 mRNA expression and DNA promoter methylation. The role of ACAT1 in NPC proliferation was examined by CCK8 and colony formation assays in vitro and tumorigenicity in vivo. The wound healing and transwell assays were used for analyzing the migratory and invasive ability. cDNA microarray analysis was performed to identify the genes involved in epithelial-mesenchymal transition and dysregulated by ACAT1. These changes were further confirmed by western blot. Results We found that ACAT1 is inactivated in NPC cell lines and primary tissues. DNA microarray data showed higher methylation in the CpG island region of ACAT1 in NPC than normal tissues. The demethylating reagent 5-aza-dC significantly restored the transcription of ACAT1 in NPC cell lines, suggesting that ACAT1 was inactivated by DNA promoter hypermethylation. Ectopic overexpression of ACAT1 remarkably suppressed the proliferation and colony formation of NPC cells in vitro. As well, the tumorigenesis of NPC cells overexpressing ACAT1 was decreased in vivo. In addition, the migratory and invasive capacities of NPC cells was inhibited by ACAT1 overexpression. Importantly, the higher level of ACAT1 was accompanied by an increased expression of CDH1, EPCAM, and a decreased expression of vimentin and SPARC. This strongly indicates that ACAT1 is able to affect the epithelial-mesenchymal transition in NPC, thereby controlling cellular motility. In addition, we found that ACAT1 expression increases the intracellular level of β-HB. Moreover, exogenous β-HB remarkably inhibits the growth of NPC cells in a dose-dependent manner. Conclusions We have discovered that the ketone body metabolism enzyme ACAT1 is epigenetically downregulated in NPC and acts as a potential tumor suppressor in NPC. Our findings highlight the possibility of using the modulation of ketone body metabolism as effective adjuvant therapy for NPC.