Role of β-hydroxybutyrate, its polymer poly-β-hydroxybutyrate and inorganic polyphosphate in mammalian health and disease

Abstract

We provide a comprehensive review of the role of β-hydroxybutyrate (β-OHB), its linear polymer poly-β-hydroxybutyrate (PHB), and inorganic polyphosphate (polyP) in mammalian health and disease. β-OHB is a metabolic intermediate that constitutes 70% of ketone bodies produced during ketosis. Although ketosis has been generally considered as an unfavorable pathological state (e.g., diabetic ketoacidosis in type-1 diabetes mellitus), it has been suggested that induction of mild hyperketonemia may have certain therapeutic benefits. β-OHB is synthesized in the liver from acetyl-CoA by β-OHB dehydrogenase and can be used as alternative energy source. Elevated levels of PHB are associated with pathological states. In humans, short-chain, complexed PHB (cPHB) is found in a wide variety of tissues and in atherosclerotic plaques. Plasma cPHB concentrations correlate strongly with atherogenic lipid profiles, and PHB tissue levels are elevated in type-1 diabetic animals. However, little is known about mechanisms of PHB action especially in the heart. In contrast to β-OHB, PHB is a water-insoluble, amphiphilic polymer that has high intrinsic viscosity and salt-solvating properties. cPHB can form non-specific ion channels in planar lipid bilayers and liposomes. PHB can form complexes with polyP and Ca2+ which increases membrane permeability. The biological roles played by polyP, a ubiquitous phosphate polymer with ATP-like bonds, have been most extensively studied in prokaryotes, however polyP has recently been linked to a variety of functions in mammalian cells, including blood coagulation, regulation of enzyme activity in cancer cells, cell proliferation, apoptosis and mitochondrial ion transport and energy metabolism. Recent evidence suggests that polyP is a potent activator of the mitochondrial permeability transition pore in cardiomyocytes and may represent a hitherto unrecognized key structural and functional component of the mitochondrial membrane system.

Sirtuin 3 Mediates Neuroprotection of Ketones against Ischemic Stroke

“…Two main ketone bodies, beta-hydroxybutyrate (BHB) and acetoacetate (ACA) which we named ketones, are generally regarded as energy carriers. 6 Ketones are consumed by the brain as a main source of energy source when glucose is limited. 7 Our previous in vitro data showed that ketones decreased the NADH level when neurons were subjected to glutamate excitotoxicity.…”

Ketone body 3‐hydroxybutyrate mimics calorie restriction via the Nrf2 activator, fumarate, in the retina

“…We found that 3HB treatment with or without CR elevated retinal fumarate accompanied by TCA cycle`s enzymes involved in ketolysis and fumarate synthesis, being independent of changes in the energy status, indicating that the late phase of the TCA cycle rather than the first phase is essential for fumarate elevation. In addition, the energy substrates responded to gluconeogenesis other than ketone bodies, fatty acids, amino acids, and carbohydrates, and they did not share intermediate conversion processes of the TCA cycle in the course of entry into this cycle (Dedkova & Blatter, 2014). Thus, herein, the elevation of the Nrf2 activator, fumarate, may be due to the unique characteristics of ketone metabolism, namely the activation of TCA cycle flux by the upregulation of a concomitant process of TCA cycle intermediate conversion and ketolysis in response to prominent sustained supplementation of 3HB in an energy shortage.…”

Acetylation mediates Cx43 reduction caused by electrical stimulation

“…Intriguingly, it has been recently reported that β-hydroxybutyrate, a fundamental contributor to cardiac energy metabolism in conditions of prolonged exercise [32] can cause HDAC inhibition and consequent protection against oxidative stress [33]. It is therefore conceivable that the factor linking electrical activity to reduced HDAC activity is a metabolic factor.…”