收稿日期: 2023-07-26
网络出版日期: 2024-01-10
基金资助
国家自然科学基金项目(31900950);自贡市重点科技计划项目(2022ZCNKY07)
Research progress of exogenous ketone body 3⁃hydroxybutyrate supplementation for human disease treatment
Received date: 2023-07-26
Online published: 2024-01-10
3羟基丁酸（3HB）是具有羟基结构的阴离子小分子酸性代谢物，存在两种对映体，与细胞的生长、增殖和抗氧化应激等有关，且在一定浓度范围内具有良好的生物安全性。除了早期的癫痫治疗，随着近些年生酮饮食的流行，人们逐步发现外源性补充3HB与多种代谢疾病的治疗存在关联。本文阐述3HB的生理功能、理化特征、毒理及生物安全性，及其作为潜在的药物分子在癫痫、减肥（体重控制）、全身性炎症、失血性休克、癌症、炎症性肠病、动脉粥样硬化、糖尿病、骨质疏松、神经疾病（如帕金森病、阿尔茨海默病和亨廷顿症）、肌肉萎缩症、新冠肺炎、抗衰老等医学诸多领域的应用进展。外源性补充3HB对多种疾病存在治疗与预防作用，具有潜在的临床转化意义，同时也存在一定的局限性。本文为人类外源性补充酮体3羟基丁酸用于部分疾病治疗提供参考方案。
魏岱旭 , 刘宇 , 周文辉 , 刘召平 . 外源性补充酮体3羟基丁酸用于疾病治疗的研究进展[J]. 实用医学杂志, 2023 , 39(24) : 3290 -3296 . DOI: 10.3969/j.issn.1006-5725.2023.24.025
3?hydroxybutyrate （3HB）， an anionic small molecule acid metabolite with a hydroxyl group， is a chiral molecule that exists in two enantiomeric forms. It is associated with cell growth， proliferation， and anti?oxidative stress， and demonstrates good biosafety when used within a specific range. In addition to epilepsy treatment， with the popularity of ketogenic diet in recent years， exogenous supplementation of 3HB for human has been gradually found to be associated with a variety of metabolic diseases. This review describes the physiological function， physicochemical characteristics， toxicology and biological safety of 3HB， and its applications as potential drug molecules in epilepsy， weight?loss （or weight control）， systemic inflammation， hemorrhagic shock， cancer， inflammatory bowel disease， atherosclerosis， diabetes， osteoporosis， neurological diseases （e.g.， Parkinson′s disease， Alzheimer′s disease and Huntington′s disease）， muscular dystrophy， COVID?19， anti?aging and many other medical fields. This review also focuses on the discussion and prospect of the new methods and the potential limitations of exogenous 3HB supplementation for clinical transformation.
| 1 | MOLLER N. Ketone Body， 3-Hydroxybutyrate： Minor Metabolite- Major Medical Manifestations ［J］. J Clin Endocrinol Metab， 2020， 105（9）：dgaa370. |
| 2 | WEI D X， DAO J W， LIU H W， et al. Suspended polyhydroxyalkanoate microspheres as 3D carriers for mammalian cell growth ［J］. Artif Cells Nanomed Biotechnol， 2018， 46（sup2）： 473-483. |
| 3 | WEI D X， DAO J W， CHEN G Q. A Micro-Ark for Cells： Highly Open Porous Polyhydroxyalkanoate Microspheres as Injectable Scaffolds for Tissue Regeneration ［J］. Adv Mater， 2018， 30（31）： e1802273. |
| 4 | WANG Z Y， ZHANG X W， DING Y W， et al. Natural biopolyester microspheres with diverse structures and surface topologies as micro-devices for biomedical applications ［J］. Smart Mater Med， 2022，7：4. |
| 5 | XIANG Y， WANG Q Q， LAN X Q， et al. Function and treatment strategies of β-hydroxybutyrate in aging ［J］. Smart Mater Med， 2023，4：160-172. |
| 6 | PAWAN G， SEMPLE S. Effect of 3-hydroxybutyrate in obese subjects on very-low-energy diets and during therapeutic starvation ［J］. Lancet， 1983， 321（8314-8315）： 15-17. |
| 7 | WANG B L， WU J F， XIAO D， et al. 3‐hydroxybutyrate in the brain： Biosynthesis， function， and disease therapy ［J］. Brain‐X， 2023， 1（1）：doi.org/10.1002/brx2.6. |
| 8 | NEWMAN J C， VERDIN E. beta-Hydroxybutyrate： A Signaling Metabolite ［J］. Annu Rev Nutr， 2017， 37： 51-76. |
| 9 | KIMURA I， INOUE D， MAEDA T， et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 （GPR41） ［J］. Proc Natil Acad Sci U S A， 2011， 108（19）： 8030-8035. |
| 10 | YUDKOFF M， DAIKHIN Y， NISSIM I， et al. Brain amino acid metabolism and ketosis ［J］. J Neurosci Res， 2001， 66（2）： 272-281. |
| 11 | ROJASMORALES P， PEDRAZACHAVERRI J， TAPIA E. Ketone bodies， stress response， and redox homeostasis ［J］. Redox Biol， 2020， 29： 101395. |
| 12 | HARTMAN A L， VINING E P. Clinical aspects of the ketogenic diet ［J］. Epilepsia， 2007， 48（1）： 31-42. |
| 13 | HYDE P N， SAPPER T N， CRABTREE C D， et al. Dietary carbohydrate restriction improves metabolic syndrome independent of weight loss ［J］. JCI Insight， 2019， 4（12）：e128308. |
| 14 | ZHANG Y， ZHOU S， ZHOU Y， et al. Altered gut microbiome composition in children with refractory epilepsy after ketogenic diet ［J］. Epilepsy Res， 2018， 145： 163-168. |
| 15 | THOMSEN H H， RITTIG N， JOHANNSEN M， et al. Effects of 3-hydroxybutyrate and free fatty acids on muscle protein kinetics and signaling during LPS-induced inflammation in humans： anticatabolic impact of ketone bodies ［J］. Am J Clin Nutr， 2018， 108（4）： 857-867. |
| 16 | OFFERMANNS S. Hydroxy-Carboxylic Acid Receptor Actions in Metabolism ［J］. Trends Endocrinol Metab， 2017， 28（3）： 227-236. |
| 17 | GRAFF E C， FANG H， WANDERS D， et al. Anti-inflammatory effects of the hydroxycarboxylic acid receptor 2 ［J］. Metabolism， 2016， 65（2）： 102-113. |
| 18 | YOUM Y H， NGUYEN K Y， GRANT R W， et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease ［J］. Nat Med， 2015， 21（3）： 263-269. |
| 19 | GOLDBERG E L， ASHER J L， MOLONY R D， et al. beta-Hydroxybutyrate Deactivates Neutrophil NLRP3 Inflammasome to Relieve Gout Flares ［J］. Cell Rep， 2017， 18（9）： 2077-2087. |
| 20 | KAJITANI N， IWATA M， MIURA A， et al. Prefrontal cortex infusion of beta-hydroxybutyrate， an endogenous NLRP3 inflammasome inhibitor， produces antidepressant-like effects in a rodent model of depression ［J］. Neuropsychopharmacol Rep， 2020， 40（2）： 157-165. |
| 21 | LUO S， YANG M， HAN Y， et al. beta-Hydroxybutyrate against Cisplatin-Induced acute kidney injury via inhibiting NLRP3 inflammasome and oxidative stress ［J］. Int Immunopharmacol， 2022， 111： 109101. |
| 22 | SHIDO O， NAGASAKA T， WATANABE T. Blunted febrile response to intravenous endotoxin in starved rats ［J］. J Appl Physiol （1985）， 1989， 67（3）： 963-969. |
| 23 | JOHNSON J B， SUMMER W， CUTLER R G， et al. Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma ［J］. Free Radic Biol Med， 2007， 42（5）： 665-674. |
| 24 | MULIER K E， LEXCEN D R， LUZCEK E， et al. Treatment with beta-hydroxybutyrate and melatonin is associated with improved survival in a porcine model of hemorrhagic shock ［J］. Resuscitation， 2012， 83（2）： 253-258. |
| 25 | WOLF A， THAKRAL S， MULIER K E， et al. Evaluation of novel formulations of d-beta-hydroxybutyrate and melatonin in a rat model of hemorrhagic shock ［J］. Int J Pharma， 2018， 548（1）： 104-112. |
| 26 | FENG S， WANG H， LIU J， et al. Multi-dimensional roles of ketone bodies in cancer biology： Opportunities for cancer therapy ［J］. Pharmacol Res， 2019， 150： 104500. |
| 27 | LI Z， ZHANG S， ZHANG Y， et al. Applications and Mechanism of 3-Hydroxybutyrate （3HB） for Prevention of Colonic Inflammation and Carcinogenesis as a Food Supplement ［J］. Mol Nutr Food Res， 2021， 65（24）： e2100533. |
| 28 | DMITRIEVA-POSOCCO O， WONG A C， LUNDGREN P， et al. beta-Hydroxybutyrate suppresses colorectal cancer ［J］. Nature， 2022， 605（7908）： 160-165. |
| 29 | ZOU Z， SASAGURI S， RAJESH K G， et al. dl-3-Hydroxybutyrate administration prevents myocardial damage after coronary occlusion in rat hearts ［J］. Am J Physiol Heart Circ Physiol， 2002， 283（5）： H1968-H1974. |
| 30 | NIELSEN R， MOLLER N， GORMSEN L C， et al. Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients ［J］. Circulation， 2019， 139（18）： 2129-2141. |
| 31 | ZHANG S J， LI Z H， ZHANG Y D， et al. Ketone Body 3-Hydroxybutyrate Ameliorates Atherosclerosis via Receptor Gpr109a-Mediated Calcium Influx ［J］. Adv Sci （Weinh）， 2021， 8（9）： 2003410. |
| 32 | GREEN A， BUSTILLOS D P， MISBIN R I. β-Hydroxybutyrate increases the insulin sensitivity of adipocyte glucose transport at a postreceptor level ［J］. Diabetes， 1984， 33（11）： 1045-1050. |
| 33 | HIDAKA H， HOWARD B V， ISHIBASHI F， et al. Effect of pH and 3-hydroxybutyrate on insulin binding and action in cultured human fibroblasts ［J］. Diabetes， 1981， 30（5）： 402-406. |
| 34 | THURSTON J H， HAUHART R E， SCHIRO J A. β-Hydroxybutyrate reverses insulin-induced hypoglycemic coma in suckling-weanling mice despite low blood and brain glucose levels ［J］. Metabolic Brain Disease， 1986， 1（1）： 63-82. |
| 35 | ZHAO Y， ZOU B， SHI Z， et al. The effect of 3-hydroxybutyrate on the in vitro differentiation of murine osteoblast MC3T3-E1 and in vivo bone formation in ovariectomized rats ［J］. Biomaterials， 2007， 28（20）： 3063-3073. |
| 36 | KASHIWAYA Y， TAKESHIMA T， MORI N， et al. d-β-Hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease ［J］. Proceedings of the National Academy of Sciences， 2000， 97（10）： 5440-5444. |
| 37 | TIEU K， PERIER C， CASPERSEN C， et al. D-β-Hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease ［J］. J Clin Investi， 2003， 112（6）： 892-901. |
| 38 | LIM S， CHESSER A S， GRIMA J C， et al. D-β-hydroxybutyrate is protective in mouse models of Huntington's disease ［J］. PLoS One， 2011， 6（9）： e24620. |
| 39 | OTA M， MATSUO J， ISHIDA I， et al. Effect of a ketogenic meal on cognitive function in elderly adults： potential for cognitive enhancement ［J］. Psychopharmacology （Berl）， 2016， 233（21-22）： 3797-3802. |
| 40 | KOPPEL S J， SWERDLOW R H. Neuroketotherapeutics： A modern review of a century-old therapy ［J］. Neurochem Int， 2018， 117： 114-125. |
| 41 | JENSEN N J， NILSSON M， INGERSLEV J S， et al. Effects of beta-hydroxybutyrate on cognition in patients with type 2 diabetes ［J］. Eur J Endocrinol， 2020， 182（2）： 233-242. |
| 42 | MAALOUF M， SULLIVAN P G， DAVIS L， et al. Ketones inhibit mitochondrial production of reactive oxygen species production following glutamate excitotoxicity by increasing NADH oxidation ［J］. Neuroscience， 2007， 145（1）： 256-264. |
| 43 | SHIMAZU T， HIRSCHEY M D， NEWMAN J， et al. Suppression of oxidative stress by beta-hydroxybutyrate， an endogenous histone deacetylase inhibitor ［J］. Science， 2013， 339（6116）： 211-214. |
| 44 | SLEIMAN S F， HENRY J， AL-HADDAD R， et al. Exercise promotes the expression of brain derived neurotrophic factor （BDNF） through the action of the ketone body beta-hydroxybutyrate ［J］. Elife， 2016， 5：e15092. |
| 45 | SVART M， GORMSEN L C， HANSEN J， et al. Regional cerebral effects of ketone body infusion with 3-hydroxybutyrate in humans： Reduced glucose uptake， unchanged oxygen consumption and increased blood flow by positron emission tomography. A randomized， controlled trial ［J］. PLoS One， 2018， 13（2）： e0190556. |
| 46 | CHEN J， LI Z， ZHANG Y， et al. Mechanism of reduced muscle atrophy via ketone body （D）-3-hydroxybutyrate ［J］. Cell Biosci， 2022， 12（1）： 94. |
| 47 | LI Z， ZHANG Y， HAN M， et al. Lysine β-Hydroxybutyrylation Improves Stability of COVID-19 Antibody ［J］. Biomacromolecules， 2021， 23（1）： 454-463. |
| 48 | XU X， SUN J， SONG R， et al. Inhibition of p70 S6 kinase （S6K1） activity by A77 1726， the active metabolite of leflunomide， induces autophagy through TAK1-mediated AMPK and JNK activation ［J］. Oncotarget， 2017， 8（18）： 30438-30454. |
| 49 | RUAN H B， CRAWFORD P A. Ketone bodies as epigenetic modifiers ［J］. Curr Opin Clin Nutr Metab Care， 2018， 21（4）： 260-266. |
| 50 | PUCHALSKA P， CRAWFORD P A. Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism， Signaling， and Therapeutics ［J］. Cell Metab， 2017， 25（2）： 262-284. |
| 51 | VEECH R L， BRADSHAW P C， CLARKE K， et al. Ketone bodies mimic the life span extending properties of caloric restriction ［J］. IUBMB Life， 2017， 69（5）： 305-314. |
| 52 | EDWARDS C， CANFIELD J， COPES N， et al. D-beta-hydroxybutyrate extends lifespan in C. elegans ［J］. Aging （Albany NY）， 2014， 6（8）： 621-644. |
| 53 | ROBERTS M N， WALLACE M A， TOMILOV A A， et al. A Ketogenic Diet Extends Longevity and Healthspan in Adult Mice ［J］. Cell Metab， 2018， 27（5）： 1156. |
| 54 | NEWMAN J C， COVARRUBIAS A J， ZHAO M， et al. Ketogenic Diet Reduces Midlife Mortality and Improves Memory in Aging Mice ［J］. Cell Metab， 2017， 26（3）： 547-557 e8. |
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