3-hydroxybutyrate (3HB), or BHB, is an anionic small molecule acid metabolite with a hydroxyl group. 3HB is the major ketone body that is distributed in the human brain and its primary energy source when glucose is absent. A better understanding of 3HB and how to adapt neuronal response mechanisms is expected to facilitate the development of new interventions to promote cognitive brain function and prevent neurodegenerative diseases. It provides important concepts for the clinical application of 3HB therapy. This review summarizes the distribution of 3HB in the brain, its properties, and its mechanism in brain and nerve regulation. We focus on 3HB biosynthesis in natural human cells and engineered bacteria via synthetic biology platforms and 3HB treatment in various brain and nerve diseases, including epilepsy, multiple sclerosis, stroke, Parkinson's disease, Alzheimer's disease, Huntington's disease, depressive disorder, and schizophrenia. Ultimately, this review explores the future development trend of 3HB as a potential smallmolecule drug for brain and nerve diseases.
K E Y W O R D S3-hydroxybutyrate, ketogenic diet, ketone body, polyhydroxyalkanoates, synthetic biology
| INTRODUCTION3-hydroxybutyrate (3HB), or BHB, is an important ketone body (KB) mainly distributed in the liver, muscle, and brain. [1] Under prolonged fasting and starvation conditions, KBs meet up to ~60% of the brain's energy requirements. [2] 3HB is mainly synthesized in the liver via fatty acid oxidation. [3] It is present in the adipose tissue and human milk and is required for converting ketogenic amino acids. [4] In vitro studies have shown that 3HB can be synthesized endogenously in astrocytes, the only cell type in the brain that is able to oxidize fatty acids. [5] However, how 3HB is metabolized in the brain using free fatty acids remains unknown. Besides providing energy, 3HB also plays an important role in several signaling pathways, such as inflammation, oxidative stress response, K +adenosine triphosphate (K + -ATP) channels, Ca 2+ channels, histone acetylation, and G protein-coupled receptors.In addition, 3HB is the primary degradation product of novel biomaterial polyhydroxyalkanoates (PHAs). [6] Compared to small acidic polylactic acid [7,8] and polycaprolactone molecules, [9,10] the moderate acidity [11] and minimal tissue rejection [12,13] of 3HB slowly released from PHAs [14] can Bing-Long Wang and Jian-Fei Wu are equal contributors.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.