β-hydroxybutyrate: Much more than a metabolite

Diabetes Research and Clinical Practice

Volumn 106, Issue 2, 2014, Pages 173-181

  Newman, John C ^a   Verdin, Eric ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Acetylation; Epigenetics; HDAC; Ketone bodies; Low carbohydrate

Indexed keywords

3 HYDROXYBUTYRIC ACID; 3 HYDROXYBUTYRIC ACID RECEPTOR; HISTONE DEACETYLASE 1; KETONE BODY; RECEPTOR; UNCLASSIFIED DRUG;

CHEMICAL BINDING; ENZYME INHIBITION; GENE EXPRESSION; HUMAN; LOW CARBOHYDRATE DIET; METABOLIC DISORDER; METABOLISM; METABOLITE; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PATHOGENESIS; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION; ADIPOCYTE;

3-HYDROXYBUTYRIC ACID; ADIPOCYTES; DIABETES MELLITUS, TYPE 2; HUMANS; SIGNAL TRANSDUCTION;

EID: 84920587151     PISSN: 01688227     EISSN: 18728227     Source Type: Journal    
DOI: 10.1016/j.diabres.2014.08.009     Document Type: Review

References (94)

1. Zimmet P.Z., Magliano D.J., Herman W.H., Shaw J.E. Diabetes: a 21st century challenge. Lancet Diabetes Endocrinol 2014, 2:56-64.
2. Shyh-Chang N., Locasale J.W., Lyssiotis C.A., Zheng Y., Teo R.Y., Ratanasirintrawoot S., et al. Influence of threonine metabolism on S-adenosylmethionine and histone methylation. Science 2013, 339:222-226.
3. Shimazu T., Hirschey M.D., Newman J., He W., Shirakawa K., Le Moan N., et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 2013, 339:211-214.
4. Stein L.R., Imai S. The dynamic regulation of NAD metabolism in mitochondria. Trends Endocrinol Metab 2012, 23:420-428.
5. Imai S.I., Guarente L. NAD and sirtuins in aging and disease. Trends Cell Biol 2014, 24(8):464-471.
6. Gut P., Verdin E. The nexus of chromatin regulation and intermediary metabolism. Nature 2013, 502:489-498.
7. Berg J.M., Tymoczko J.L., Stryer L. Biochemistry 2012, W.H. Freeman, New York. 7th ed.
8. Cahill G.F., Herrera M.G., Morgan A.P., Soeldner J.S., Steinke J., Levy P.L., et al. Hormone-fuel interrelationships during fasting. J Clin Invest 1966, 45:1751-1769.
9. Robinson A.M., Williamson D.H. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev 1980, 60:143-187.
10. Kim do Y., Rho J.M. The ketogenic diet and epilepsy. Curr Opin Clin Nutr Metab Care 2008, 11:113-120.
11. Newman J.C., Verdin E. Ketone bodies as signaling metabolites. Trends Endocrinol Metab 2014, 25:42-52.
12. Hegardt F.G. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis. Biochem J 1999, 338(Pt 3):569-582.
13. Wolfrum C., Besser D., Luca E., Stoffel M. Insulin regulates the activity of forkhead transcription factor Hnf-3beta/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization. Proc Natl Acad Sci U S A 2003, 100:11624-11629.
14. von Meyenn F., Porstmann T., Gasser E., Selevsek N., Schmidt A., Aebersold R., et al. Glucagon-induced acetylation of Foxa2 regulates hepatic lipid metabolism. Cell Metab 2013, 17:436-447.
15. Wolfrum C., Asilmaz E., Luca E., Friedman J.M., Stoffel M. Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes. Nature 2004, 432:1027-1032.
16. Howell J.J., Manning B.D. mTOR couples cellular nutrient sensing to organismal metabolic homeostasis. Trends Endocrinol Metab 2011, 22:94-102.
17. Sengupta S., Peterson T.R., Laplante M., Oh S., Sabatini D.M. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 2010, 468:1100-1104.
18. Badman M.K., Pissios P., Kennedy A.R., Koukos G., Flier J.S., Maratos-Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 2007, 5:426-437.
19. Quant P.A., Tubbs P.K., Brand M.D. Glucagon activates mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase in vivo by decreasing the extent of succinylation of the enzyme. Eur J Biochem 1990, 187:169-174.
20. Shimazu T., Hirschey M.D., Hua L., Dittenhafer-Reed K.E., Schwer B., Lombard D.B., et al. SIRT3 deacetylates mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab 2010, 12:654-661.
21. Rardin M.J., Newman J.C., Held J.M., Cusack M.P., Sorensen D.J., Li B., et al. Label-free quantitative proteomics of the lysine acetylome in mitochondria identifies substrates of SIRT3 in metabolic pathways. Proc Natl Acad Sci 2013, 110(16):6601-6606.
22. Rardin M.J., He W., Nishida Y., Newman J.C., Carrico C., Danielson S.R., et al. SIRT5 regulates the mitochondrial lysine succinylome and metabolic networks. Cell Metab 2013, 18:920-933.
23. Gregoretti I.V., Lee Y.M., Goodson H.V. Molecular evolution of the histone deacetylase family: functional implications of phylogenetic analysis. J Mol Biol 2004, 338:17-31.
24. Yang X.J., Seto E. The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men. Nat Rev Mol Cell Biol 2008, 9:206-218.
25. Mihaylova M.M., Shaw R.J. Metabolic reprogramming by class I and II histone deacetylases. Trends Endocrinol Metab 2013, 24:48-57.
26. New M., Olzscha H., La Thangue N.B. HDAC inhibitor-based therapies: can we interpret the code. Mol Oncol 2012, 6:637-656.
27. Glozak M.A., Sengupta N., Zhang X., Seto E. Acetylation and deacetylation of non-histone proteins. Gene 2005, 363:15-23.
28. Kenyon C.J. The genetics of ageing. Nature 2010, 464:504-512.
29. Mihaylova M.M., Vasquez D.S., Ravnskjaer K., Denechaud P.D., Yu R.T., Alvarez J.G., et al. Class IIa histone deacetylases are hormone-activated regulators of FOXO and mammalian glucose homeostasis. Cell 2011, 145:607-621.
30. Knutson S.K., Chyla B.J., Amann J.M., Bhaskara S., Huppert S.S., Hiebert S.W. Liver-specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. Embo J 2008, 27:1017-1028.
31. Fajas L., Egler V., Reiter R., Hansen J., Kristiansen K., Debril M.B., et al. The retinoblastoma-histone deacetylase 3 complex inhibits PPARgamma and adipocyte differentiation. Dev Cell 2002, 3:903-910.
32. Bhaskara S., Knutson S.K., Jiang G., Chandrasekharan M.B., Wilson A.J., Zheng S., et al. Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 2010, 18:436-447.
33. Gao Z., Yin J., Zhang J., Ward R.E., Martin R.J., Lefevre M., et al. Butyrate improves insulin sensitivity and increases energy expenditure in mice. Diabetes 2009, 58:1509-1517.
34. Galmozzi A., Mitro N., Ferrari A., Gers E., Gilardi F., Godio C., et al. Inhibition of class I histone deacetylases unveils a mitochondrial signature and enhances oxidative metabolism in skeletal muscle and adipose tissue. Diabetes 2013, 62:732-742.
35. Li H., Gao Z., Zhang J., Ye X., Xu A., Ye J., et al. Sodium butyrate stimulates expression of fibroblast growth factor 21 in liver by inhibition of histone deacetylase 3. Diabetes 2012, 61:797-806.
36. Zeng Z., Liao R., Yao Z., Zhou W., Ye P., Zheng X., et al. Three single nucleotide variants of the HDAC gene are associated with type 2 diabetes mellitus in a Chinese population: a community-based case-control study. Gene 2014, 533:427-433.
37. Zimmermann S., Kiefer F., Prudenziati M., Spiller C., Hansen J., Floss T., et al. Reduced body size and decreased intestinal tumor rates in HDAC2-mutant mice. Cancer Res 2007, 67:9047-9054.
38. Giacco F., Brownlee M. Oxidative stress and diabetic complications. Circ Res 2010, 107:1058-1070.
39. Advani A., Huang Q., Thai K., Advani S.L., White K.E., Kelly D.J., et al. Long-term administration of the histone deacetylase inhibitor vorinostat attenuates renal injury in experimental diabetes through an endothelial nitric oxide synthase-dependent mechanism. Am J Pathol 2011, 178:2205-2214.
40. Noh H., Oh E.Y., Seo J.Y., Yu M.R., Kim Y.O., Ha H., et al. Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta1-induced renal injury. Am J of Physiol Ren Physiol. 2009, 297:F729-F739.
41. Graff J., Tsai L.H. Histone acetylation: molecular mnemonics on the chromatin. Nat Rev Neurosci 2013, 14:97-111.
42. Zhang L.T., Yao Y.M., Lu J.Q., Yan X.J., Yu Y., Sheng Z.Y. Sodium butyrate prevents lethality of severe sepsis in rats. Shock 2007, 27:672-677.
43. Ni Y.F., Wang J., Yan X.L., Tian F., Zhao J.B., Wang Y.J., et al. Histone deacetylase inhibitor, butyrate, attenuates lipopolysaccharide-induced acute lung injury in mice. Respir Res 2010, 11:33.
44. Masuda R., Monahan J.W., Kashiwaya Y. D-beta-hydroxybutyrate is neuroprotective against hypoxia in serum-free hippocampal primary cultures. J Neurosci Res 2005, 80:501-509.
45. Samoilova M., Weisspapir M., Abdelmalik P., Velumian A.A., Carlen P.L. Chronic in vitro ketosis is neuroprotective but not anti-convulsant. J Neurochem 2010, 113:826-835.
46. Poplawski M.M., Mastaitis J.W., Isoda F., Grosjean F., Zheng F., Mobbs C.V. Reversal of diabetic nephropathy by a ketogenic diet. PLoS One 2011, 6:e18604.
47. Klein A.H., Wendroth S.M., Drewes L.R., Andrews M.T. Small-volume d-beta-hydroxybutyrate solution infusion increases survivability of lethal hemorrhagic shock in rats. Shock 2010, 34:565-572.
48. Mulier K.E., Lexcen D.R., Luzcek E., Greenberg J.J., Beilman G.J. Treatment with beta-hydroxybutyrate and melatonin is associated with improved survival in a porcine model of hemorrhagic shock. Resuscitation 2012, 83:253-258.
49. Zou Z., Sasaguri S., Rajesh K.G., Suzuki R. dl-3-Hydroxybutyrate administration prevents myocardial damage after coronary occlusion in rat hearts. Am J Physiol Heart Circ Physiol 2002, 283:H1968-H1974.
50. Puchowicz M.A., Zechel J.L., Valerio J., Emancipator D.S., Xu K., Pundik S., et al. Neuroprotection in diet-induced ketotic rat brain after focal ischemia. J Cereb Blood Flow Metab 2008, 28:1907-1916.
51. Tai K.K., Nguyen N., Pham L., Truong D.D. Ketogenic diet prevents cardiac arrest-induced cerebral ischemic neurodegeneration. J Neural Transm 2008, 115:1011-1017.
52. Blad C.C., Tang C., Offermanns S. G protein-coupled receptors for energy metabolites as new therapeutic targets. Nat Rev Drug Discov 2012, 11:603-619.
53. Layden B.T., Angueira A.R., Brodsky M., Durai V., Lowe W.L. Short chain fatty acids and their receptors: new metabolic targets. Transl Res 2013, 161:131-140.
54. Tunaru S., Kero J., Schaub A., Wufka C., Blaukat A., Pfeffer K., et al. PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect. Nat Med 2003, 9:352-355.
55. Taggart A.K., Kero J., Gan X., Cai T.Q., Cheng K., Ippolito M., et al. (D)-beta-Hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J Biol Chem 2005, 280:26649-26652.
56. Offermanns S., Colletti S.L., Lovenberg T.W., Semple G., Wise A., IJzerman A.P. International Union of Basic and Clinical Pharmacology. LXXXII: nomenclature and classification of hydroxy-carboxylic acid receptors (GPR81, GPR109A, and GPR109B). Pharmacol Rev 2011, 63:269-290.
57. Boden G. Obesity, insulin resistance and free fatty acids. Curr Opin Endocrinol Diabetes Obes 2011, 18:139-143.
58. Dobbins R.L., Shearn S.P., Byerly R.L., Gao F.F., Mahar K.M., Napolitano A., et al. GSK256073, a selective agonist of G-protein coupled receptor 109A (GPR109A) reduces serum glucose in subjects with type 2 diabetes mellitus. Diabetes Obes Metab 2013, 15:1013-1021.
59. Lukasova M., Malaval C., Gille A., Kero J., Offermanns S. Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells. J Clin Invest 2011, 121:1163-1173.
60. Zandi-Nejad K., Takakura A., Jurewicz M., Chandraker A.K., Offermanns S., Mount D., et al. The role of HCA2 (GPR109A) in regulating macrophage function. FASEB J 2013, 27:4366-4374.
61. Kimura I., Inoue D., Maeda T., Hara T., Ichimura A., Miyauchi S., et al. Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41). Proc Natl Acad Sci U S A 2011, 108:8030-8035.
62. Won Y.J., Lu V.B., Puhl H.L., Ikeda S.R. beta-Hydroxybutyrate modulates N-type calcium channels in rat sympathetic neurons by acting as an agonist for the G-protein-coupled receptor FFA3. J Neurosci 2013, 33:19314-19325.
63. Katada S., Imhof A., Sassone-Corsi P. Connecting threads: epigenetics and metabolism. Cell 2012, 148:24-28.
64. He W., Newman J.C., Wang M.Z., Ho L., Verdin E. Mitochondrial sirtuins: regulators of protein acylation and metabolism. Trends Endocrinol Metab 2012, 23:467-476.
65. Hirschey M.D., Shimazu T., Goetzman E., Jing E., Schwer B., Lombard D.B., et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 2010, 464:121-125.
66. Madiraju P., Pande S.V., Prentki M., Madiraju S.R. Mitochondrial acetylcarnitine provides acetyl groups for nuclear histone acetylation. Epigenetics 2009, 4:399-403.
67. Wellen K.E., Hatzivassiliou G., Sachdeva U.M., Bui T.V., Cross J.R., Thompson C.B. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 2009, 324:1076-1080.
68. Muoio D.M., Noland R.C., Kovalik J.P., Seiler S.E., Davies M.N., DeBalsi K.L., et al. Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. Cell Metab 2012, 15:764-777.
69. Weinert B.T., Scholz C., Wagner S.A., Iesmantavicius V., Su D., Daniel J.A., et al. Lysine succinylation is a frequently occurring modification in prokaryotes and eukaryotes and extensively overlaps with acetylation. Cell Rep 2013, 4:842-851.
70. Quant P.A., Tubbs P.K., Brand M.D. Treatment of rats with glucagon or mannoheptulose increases mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase activity and decreases succinyl-CoA content in liver. Biochem J 1989, 262:159-164.
71. Yoshino J., Mills K.F., Yoon M.J., Imai S. Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab 2011, 14:528-536.
72. Fontana L. Excessive adiposity, calorie restriction, and aging. Jama 2006, 295:1577-1578.
73. Hatori M., Vollmers C., Zarrinpar A., DiTacchio L., Bushong E.A., Gill S., et al. Time-restricted feeding without reducing caloric intake prevents metabolic diseases in mice fed a high-fat diet. Cell Metab 2012, 15:848-860.
74. Hartman A.L., Vining E.P. Clinical aspects of the ketogenic diet. Epilepsia 2007, 48:31-42.
75. Mobbs C.V., Mastaitis J., Isoda F., Poplawski M. Treatment of diabetes and diabetic complications with a ketogenic diet. J Child Neurol 2013, 28:1009-1014.
76. Borghjid S., Feinman R.D. Response of C57Bl/6 mice to a carbohydrate-free diet. Nutr Metab (Lond). 2012, 9:69.
77. Bainbridge H.W. The reduced sensitivity to insulin of rats and mice fed on a carbohydrate-free, excess-fat diet. J Physiol 1925, 60:293-300.
78. Burcelin R., Crivelli V., Dacosta A., Roy-Tirelli A., Thorens B. Heterogeneous metabolic adaptation of C57BL/6J mice to high-fat diet. Am J Physiol Endocrinol Metab 2002, 282:E834-E842.
79. Kinzig K.P., Honors M.A., Hargrave S.L. Insulin sensitivity and glucose tolerance are altered by maintenance on a ketogenic diet. Endocrinology 2010, 151:3105-3114.
80. Garbow J.R., Doherty J.M., Schugar R.C., Travers S., Weber M.L., Wentz A.E., et al. Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet. Am J Physiol Gastrointest Liver Physiol 2011, 300:G956-G967.
81. Kennedy A.R., Pissios P., Otu H., Roberson R., Xue B., Asakura K., et al. A high-fat, ketogenic diet induces a unique metabolic state in mice. Am J Physiol Endocrinol Metab 2007, 292:E1724-E1739.
82. Badman M.K., Kennedy A.R., Adams A.C., Pissios P., Maratos-Flier E. A very low carbohydrate ketogenic diet improves glucose tolerance in ob/ob mice independently of weight loss. Am J Physiol Endocrinol Metab 2009, 297:E1197-E1204.
83. Hirschey M.D., Shimazu T., Jing E., Grueter C.A., Collins A.M., Aouizerat B., et al. SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol Cell 2011, 44:177-190.
84. Jornayvaz F.R., Jurczak M.J., Lee H.Y., Birkenfeld A.L., Frederick D.W., Zhang D., et al. A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain. Am J Physiol Endocrinol Metab 2010, 299:E808-E815.
85. Srivastava S., Baxa U., Niu G., Chen X., Veech R.L. A ketogenic diet increases brown adipose tissue mitochondrial proteins and UCP1 levels in mice. IUBMB Life 2013, 65:58-66.
86. Freedland S.J., Mavropoulos J., Wang A., Darshan M., Demark-Wahnefried W., Aronson W.J., et al. Carbohydrate restriction, prostate cancer growth, and the insulin-like growth factor axis. Prostate 2008, 68:11-19.
87. Mavropoulos J.C., Buschemeyer W.C., Tewari A.K., Rokhfeld D., Pollak M., Zhao Y., et al. The effects of varying dietary carbohydrate and fat content on survival in a murine LNCaP prostate cancer xenograft model. Cancer Prev Res (Phila) 2009, 2:557-565.
88. McDaniel S.S., Rensing N.R., Thio L.L., Yamada K.A., Wong M. The ketogenic diet inhibits the mammalian target of rapamycin (mTOR) pathway. Epilepsia 2011, 52:e7-e11.
89. Nordmann A.J., Nordmann A., Briel M., Keller U., Yancy W.S., Brehm B.J., et al. Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials. Arch Intern Med 2006, 166:285-293.
90. Paoli A., Rubini A., Volek J.S., Grimaldi K.A. Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate (ketogenic) diets. Eur J Clin Nutr 2013, 67:789-796.
91. Ajala O., English P., Pinkney J. Systematic review and meta-analysis of different dietary approaches to the management of type 2 diabetes. Am J Clin Nutr 2013, 97:505-516.
92. Harvie M., Wright C., Pegington M., McMullan D., Mitchell E., Martin B., et al. The effect of intermittent energy and carbohydrate restriction v. daily energy restriction on weight loss and metabolic disease risk markers in overweight women. Br J Nutr 2013, 1-14.
93. Westman E.C., Yancy W.S., Mavropoulos J.C., Marquart M., McDuffie J.R. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutr Metab (Lond) 2008, 5:36.
94. Frigolet M.E., Ramos Barragan V.E., Tamez Gonzalez M. Low-carbohydrate diets: a matter of love or hate. Ann. Nutr. Metab. 2011, 58:320-334.