Ketones in the Life Sciences – Biochemistry, Metabolism, and Medicinal Significances

Abstract

Being very soluble in aqueous solutions with relatively low toxicity and high stability, ketones play central roles in intermediary metabolism and physiological homeostasis. In mammals, lipid catabolism by β-oxidation of fatty acids produces acetyl-CoA, which is converted to ketone bodies in a process known as ketogenesis. During periods of low glucose availability, the synthesis of ketones from lipid sources represents a metabolic shift. Ketone bodies are formed in the hepatic tissues and travel to extrahepatic tissues to serve as an alternative energy source to carbohydrates during periods of fasting, post-exercise, pregnancy, and starvation. This is particularly important to fuel the brain in times of nutritional deprivation. Ketogenesis is hormonally upregulated by glucagon, thyroid hormone, catecholamines, and cortisol. Insulin is the primary negative regulator of this process so that low insulin levels trigger ketogenesis. Ketones can also be involved in other biological processes such as de novo lipogenesis and sterol synthesis, as well as gluconeogenesis, β-oxidation, and tricarboxylic acid cycle. Several inborn errors of metabolism highlight the importance of ketones in energy generation. The ubiquitous nature of ketones, as well as their key roles in regulation of metabolic pathways, makes them attractive targets for new drug development.