Ketone Body Metabolism and Renal Diseases

LIU Ying, MA Liang, FU Ping

Abstract

A ketogenic diet limits energy supply from glucose and stimulates lipolysis, lipid oxidation, and ketogenesis, resulting in elevated levels of ketone bodies in the bloodstream. Ketone bodies are synthesized in the mitochondrial matrix of liver cells and β-hydroxybutyric acid (BHB) is the most abundant type of ketone body. Herein, we reviewed published findings on the metabolism of ketone bodies and the role of BHB in renal diseases. Through blood circulation, ketone bodies reach metabolically active tissues and provides an alternative source of energy. BHB, being a signaling molecule, mediates various types of cellular signal transduction and participates in the development and progression of many diseases. BHB also has protective and therapeutic effects on a variety of renal diseases. BHB improves the prognosis of renal diseases, such as diabetic kidney disease, chronic kidney disease, acute kidney injury, and polycystic kidney disease, through its antioxidant, anti-inflammatory, and stress response mechanisms. Previous studies have focused on the role of ketone bodies in regulating inflammation and oxidative stress in immune cells. Investigations into the effect of elevated levels of ketone bodies on the metabolism of renal podocytes and tubular cells remain inconclusive. Further research is needed to investigate the effect of BHB on podocyte damage and podocyte senescence in renal diseases.


Keywords: Ketone body,  Renal disease,  Anti-oxidative,  Anti-inflammatory,  Review

 

Full Text:

PDF


References


LUDWIG D S， WILLETT W C， VOLEK J S， et al. Dietary fat: from foe to friend? Science，2018，362(6416): 764–770. doi: 10.1126/science. aau2096.

TUCK C J， STAUDACHER H M. The keto diet and the gut: cause for concern? Lancet Gastroenterol Hepatol，2019，4(12): 908–909. doi: 10. 1016/s2468-1253(19)30353-x.

WELLS J， SWAMINATHAN A， PASEKA J， et al. Efficacy and safety of a ketogenic diet in children and adolescents with refractory epilepsy--a review. Nutrients，2020，12(6): 1809. doi: 10.3390/nu12061809.

AUGUSTIN K， KHABBUSH A， WILLIAMS S， et al. Mechanisms of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorders. Lancet Neurol，2018，17(1): 84–93. doi: 10.1016/s1474-4422(17)30408-8.

MOLLER N. Ketone body, 3-hydroxybutyrate: minor metabolite--major medical manifestations. J Clin Endocrinol Metab，2020，105(9): dgaa370. doi: 10.1210/clinem/dgaa370.

ZHAO C， WANG H， LIU Y， et al. Biased allosteric activation of ketone body receptor HCAR2 suppresses inflammation. Mol Cell，2023，83(17): 3171–3187.e7. doi: 10.1016/j.molcel.2023.07.030.

NEWMAN J C， VERDIN E. beta-hydroxybutyrate: a signaling metabolite. Annu Rev Nutr，2017，37: 51–76. doi: 10.1146/annurev-nutr-071816-064916.

HUTTON H L， OOI J D， HOLDSWORTH S R， et al. The NLRP3 inflammasome in kidney disease and autoimmunity. Nephrology (Carlton)，2016，21(9): 736–744. doi: 10.1111/nep.12785.

FANG Y， CHEN B， GONG A Y， et al. The ketone body beta-hydroxybutyrate mitigates the senescence response of glomerular podocytes to diabetic insults. Kidney Int，2021，100(5): 1037–1053. doi: 10.1016/j.kint.2021.06.031.

TAJIMA T， YOSHIFUJI A， MATSUI A， et al. β-hydroxybutyrate attenuates renal ischemia-reperfusion injury through its anti-pyroptotic effects. Kidney Int，2019，95(5): 1120–1137. doi: 10.1016/j.kint.2018.11. 034.

CAHILL G F， Jr. Fuel metabolism in starvation. Annu Rev Nutr，2006， 26: 1–22. doi: 10.1146/annurev.nutr.26.061505.111258.

PUCHALSKA P， CRAWFORD P A. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab，2017， 25(2): 262–284. doi: 10.1016/j.cmet.2016.12.022.

PELLERIN L， BERGERSEN L H， HALESTRAP A P， et al. Cellular and subcellular distribution of monocarboxylate transporters in cultured brain cells and in the adult brain. J Neurosci Res，2005，79(1/2): 55–64. doi: 10. 1002/jnr.20307.

BARAC-NIETO M. Renal reabsorption and utilization of hydroxybutyrate and acetoacetate in starved rats. Am J Physiol，1986， 251(2 Pt 2): F257–F265. doi: 10.1152/ajprenal.1986.251.2.F257.

SINGH A K， BISHAYEE A， PANDEY A K. Targeting histone deacetylases with natural and synthetic agents: an emerging anticancer strategy. Nutrients，2018，10(6): 731. doi: 10.3390/nu10060731.

ZHANG S J， LI Z H， ZHANG Y D， et al. Ketone body 3-hydroxybutyrate ameliorates atherosclerosis via receptor Gpr109a-mediated calcium influx. Adv Sci (Weinh)，2021，8(9): 2003410. doi: 10. 1002/advs.202003410.

PARODI B， ROSSI S， MORANDO S， et al. Fumarates modulate microglia activation through a novel HCAR2 signaling pathway and rescue synaptic dysregulation in inflamed CNS. Acta Neuropathol，2015， 130(2): 279–295. doi: 10.1007/s00401-015-1422-3.

MOUTINHO M， PUNTAMBEKAR S S， TSAI A P， et al. The niacin receptor HCAR2 modulates microglial response and limits disease progression in a mouse model of Alzheimer's disease. Sci Transl Med， 2022，14(637): eabl7634. doi: 10.1126/scitranslmed.abl7634.

PEREZ-MORALES R E， Del PINO M D， VALDIVIELSO J M， et al. Inflammation in diabetic kidney disease. Nephron，2019，143(1): 12–16. doi: 10.1159/000493278.

POPLAWSKI M M， MASTAITIS J W， ISODA F， et al. Reversal of diabetic nephropathy by a ketogenic diet. PLoS One，2011，6(4): e18604. doi: 10.1371/journal.pone.0018604.

TOMITA I， KUME S， SUGAHARA S， et al. SGLT2 inhibition mediates protection from diabetic kidney disease by promoting ketone body-induced mTORC1 inhibition. Cell Metab，2020，32(3): 404–419.e6. doi: 10.1016/j.cmet.2020.06.020.

UCHIHASHI M， HOSHINO A， OKAWA Y， et al. Cardiac-specific Bdh1 overexpression ameliorates oxidative stress and cardiac remodeling in pressure overload-induced heart failure. Circ Heart Fail，2017，10(12): e004417. doi: 10.1161/CIRCHEARTFAILURE.117.004417.

KAROLAK M J， GUAY J A， OXBURGH L. Inactivation of MAP3K7 in FOXD1-expressing cells results in loss of mesangial PDGFRBeta and juvenile kidney scarring. Am J Physiol Renal Physiol，2018，315(2): F336–F344. doi: 10.1152/ajprenal.00493.2017.

CUI N， HU M， KHALIL R A. Biochemical and biological attributes of matrix metalloproteinases. Prog Mol Biol Transl Sci，2017，147: 1–73. doi: 10.1016/bs.pmbts.2017.02.005.

LUO W， YU Y， WANG H， et al. Up-regulation of MMP-2 by histone H3K9 beta-hydroxybutyrylation to antagonize glomerulosclerosis in diabetic rat. Acta Diabetol，2020，57(12): 1501–1509. doi: 10.1007/s00592-020-01552-2.

WHITE K E， BILOUS R W， MARSHALL S M， et al. Podocyte number in normotensive type 1 diabetic patients with albuminuria. Diabetes， 2002，51(10): 3083–3089. doi: 10.2337/diabetes.51.10.3083.

PAGTALUNAN M E， MILLER P L， JUMPING-EAGLE S， et al. Podocyte loss and progressive glomerular injury in type Ⅱ diabetes. J Clin Invest，1997，99(2): 342–348. doi: 10.1172/JCI119163.

MEIDENBAUER J J， TA N， SEYFRIED T N. Influence of a ketogenic diet, fish-oil, and calorie restriction on plasma metabolites and lipids in C57BL/6J mice. Nutr Metab (Lond)，2014，11: 23. doi: 10.1186/1743-7075-11-23.

ROBERTS M N， WALLACE M A， TOMILOV A A， et al. A ketogenic diet extends longevity and healthspan in adult mice. Cell Metab，2017， 26(3): 539–546.e5. doi: 10.1016/j.cmet.2017.08.005.

NEWMAN J C， COVARRUBIAS A J， ZHAO M， et al. Ketogenic diet reduces midlife mortality and improves memory in aging mice. Cell Metab，2017，26(3): 547–557.e8. doi: 10.1016/j.cmet.2017.08.004.


Refbacks

  • There are currently no refbacks.