Eric Devaney Lab - Research

Ketone Bodies

Ketone body metabolism is an evolutionary conserved metabolic pathway that allows organisms to survive prolonged periods of starvation. The three ketone bodies are beta-hydroxybutyrate (βOHB), acetoacetate (AcAc), and acetone. The major circulating ketone body is βOHB accounting for approximately 70% of all blood ketones, with its dehydrogenated form AcAc accounting for approximately 20%, and the decarboxylated acetoacetate, acetone, accounting for the rest. βOHB and AcAc are produced in the liver and released into the blood stream where they are consumed by extrahepatic organs. In healthy adults, circulating levels of βOHB are less than 0.1 millimolar. However, after about 16 hours of fasting, βOHB rises to approximately 1mM and eventually will level off between 5mM and 6mM after 5 days of fasting.

Figure 1. Glucose, Fatty Acid, and Ketone Bodies Blood Concentration During Prolonged Fasting. A. The five metabolic stages of glucose metabolism between the postabsorptive state and the near-steady state of prolonged starvation. B. Concentrations of ketone bodies and plasma free fatty acids (FFA) in transition from the postabsorptive state to 4–6 weeks of starvation. Modified from Annu. Rev. Nutr. 2006. 26:1–22.

 
A growing consensus is that metabolic perturbations influence healthy cardiac development as well as underlie many cardiovascular diseases. Because of its association with diabetic ketoacidosis, the utilization of ketone bodies by the body has a negative stigma. However, new experimental and clinical evidence suggest ketone body utilization may be cardio protective by decreasing both inflammation and oxidative stress. .

Figure 2. Sarcomere shortening in myocytes cultured with/without βOHB in RPMI media. (A) Representative ensembled average traces for 1 Hz pacing during normoxic conditions. (B) Representative ensembled average traces for 1 Hz pacing during hypoxic conditions. (C) Quantification of shortening amplitudes during normoxic conditions. (D) Quantification of shortening amplitudes during hypoxic conditions. (E) Quantification of shortening velocities during normoxic conditions. (F) Quantification of shortening velocities during hypoxic conditions. From Archives of Biochemistry and Biophysics Volume 662, 15 February 2019, Pages 143-150

 
Data from our lab suggests βOHB improves single cell excitation-coupling. This is concordant with work from other labs that show administration of exogenous βOHB improves cardiac output and even prevents the development of heart failure. Consequently, the goal of this project is to understand how ketone bodies influence normal cardiac development and excitation contraction coupling in physiological and pathological conditions using murine and human induced pluripotent stem derived cardiac myocytes as our model system.

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