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Abstract
The effects of ketone body metabolism suggests that mild ketosis may offer therapeutic potential in a variety of different common
and rare disease states. These inferences follow directly from the metabolic effects of ketosis and the higher inherent energy present
in d-b-hydroxybutyrate relative to pyruvate, the normal mitochondrial fuel produced by glycolysis leading to an increase in the DG0
of ATP hydrolysis. The large categories of disease for which ketones may have therapeutic effects are:
(1) diseases of substrate insufciency or insulin resistance,
(2) diseases resulting from free radical damage,
(3) disease resulting from hypoxia.
Current ketogenic diets are all characterized by elevations of free fatty acids, which may lead to metabolic inefciency by
activation of the PPAR system and its associated uncoupling mitochondrial uncoupling proteins. New diets comprised of ketone
bodies themselves or their esters may obviate this present difculty.
Published by Elsevier Ltd.
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Table 1
Heats of combustion of common non-nitrogenous energy substrates
Substrate
DH o kcal/mol
DH o kcal/mol C2 units
C18H32O2 Palmitate
C4H8O3 b HOButyrate
C6H12O6 Glucose
C3H4O3 Pyruvate
2384.8
487.2
669.9
278.5
298
243.6
223.6
185.7
311
In addition to their effects on mitochondrial energetics, the metabolism of ketone bodies has other effects
with therapeutic implications. Of major signicance is
the ability of ketone bodies to increase the concentrations of the metabolites of the rst third of the citric acid
cycle. Next to causing the translocation of GLUT4 from
endoplasmic to plasma membrane, one of the most
important acute metabolic effects of insulin, is the
stimulation of the activity of the pyruvate dehydrogenase multienzyme complex leading to an increased
production of mitochondrial acetyl CoA, the essential
substrate for the citric acid cycle. The metabolism of
ketone bodies or the addition of insulin to working
perfused heart both results in increases of cardiac acetyl
CoA content 1218 fold. This increase is associated with
increases of 28 fold in the cardiac content of citrate and
the other constituents of the citric acid cycle down to aketoglutarate, and including l-glutamate, an important
redox partner of a-ketoglutarate and the mitochondrial
NAD couple. Citrate is an important precursor in the
generation of cytosolic acetyl CoA for lipid and acetyl
choline biosynthesis, while l-glutamate is a necessary
precursor for GABA synthesis in neural tissue.
The metabolic effects of ketone bodies are of
particular relevance to brain metabolism, where Cahill
and his colleagues have established that over 60% of the
metabolic energy needs of brain can be supplied by
ketone bodies, rather than by glucose [11]. They have
further established that mild ketosis with blood levels of
57 mM is the normal physiological response to
prolonged fasting in man [12]. The 1.5 kg human brain
utilizes 20% of the total body oxygen consumption at
rest, requiring 100150 g of glucose per day [13].
Although man can make about 10% of the glucose to
supply brain needs during fasting from fat [14],
prolonged starvation in man leads to the excretion of
49 g of nitrogen per day which is equivalent to the
destruction of 2555 g protein/day. This amount of
protein catabolism could supply between 17 and 32 g of
glucose per day, far below the 100150 g/day required.
To supply the glucose required to support brain from
protein alone would lead to death in about 10 days
instead of the 5773 days required to cause death in a
young male of normal body composition during a total
fast [15]. Cahill also noted that in his subjects undergoing total starvation for 30 days, hunger subsided on
about the third day, coincident with the elevation of
blood ketones to 7 mM. During prolonged fasting, the
human produces about 150 g of ketone bodies per day
[16]. This suggests, that even though the Vmax of the
monocarboxylate transporter in brain is increased
during ketosis [17], the Km at the endothelial cell of
approximately 5 mM for ketone body transport of
approximately 5 mM would still dominate the ketone
effects in brain, so that a blood level only slightly below
that of 7 mM ketone bodies would be required to
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References
[1] Y. Kashiwaya, K. Sato, N. Tsuchiya, S. Thomas, D.A. Fell, R.L.
Veech, et al., Control of glucose utilization in working perfused
rat heart, J. Biol. Chem. 269 (1994) 2550225514.
[2] K. Sato, Y. Kashiwaya, C.A. Keon, N. Tsuchiya, M.T. King,
G.K. Radda, et al., Insulin, ketone bodies, and mitochondrial
energy transduction, FASEB J. 9 (1995) 651658.
[3] D.F. Horrobin, Innovation in the pharmaceutical industry, J. R.
Soc. Med. 93 (7) (2000) 341345.
[4] H.A. Krebs, R.L. Veech, Pyridine nucleotide interrelations, in: S.
Papa, J.M. Tager, E. Quagliariello, E.C. Slater (Eds.), The Energy
Level and Metabolic Control in Mitochondria, Bari, Adriatica
Editrice, 1969, pp. 329382.
[5] W.M. Clark, Oxidation Reduction Potentials of Organic Systems,
Williams and Wilkins Co., Baltimore, 1960.
[6] P. Mitchell, Chemiosmotic Coupling and Energy Transduction,
Glynn Research Ltd., Bodmin, 1968.
[7] C. Gibbons, M.G. Montgomery, A.G.W. Leslie, J.E. Walker, The
structure of the central stalk in bovine F1-ATPase at 2.4 A
resolution, Nature Struct. Biol. 7 (2000) 10551061.
[8] K. Yasuda, H. Noji, K. Kinosita Jr., M. Yoshida, F1-ATPase is a
highly efcient molecular motor that rotates with discrete 120
steps, Cell 93 (1998) 11171124.
[9] D.H. Williamson, P. Lund, H.A. Krebs, The redox state of free
nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver, Biochem. J. 103 (1967) 514527.
[10] E.A. Boehm, B.E. Jones, G.K. Radda, R.L. Veech, K. Clarke,
Increased uncoupling proteins and decreased efciency in
palmitate-perfused hyperthyroid rat heart, Am. J. Physiol Heart
Circ. Physiol 280 (3) (2001) H977H983.
[11] O.E. Owen, A.P. Morgan, H.G. Kemp, J.M. Sullivan, M.G.
Herrera, G.F. Cahill Jr., Brain metabolism during fasting, J. Clin.
Invest. 46 (1967) 15891595.
[12] G.F. Cahill Jr., Starvation in man, N. Engl. J. Med. 282 (1970)
668675.
[13] G.F. Cahill Jr., M.G. Herrera, A.P. Morgan, J.S. Soeldner,
J. Steinke, P.L. Levy, et al., Hormone-fuel interrelationships
during fasting, J. Clin. Invest 45 (11) (1966) 17511769.
[14] J.P. Casazza, M.E. Felver, R.L. Veech, The metabolism of
acetone in rat, J. Biol. Chem. 259 (1984) 231236.
[15] T.B. VanItallie, T.H. Nufert, Ketones: metabolisms Ugly
Duckling, Annu. Rev. Nutr. 61 (10) (2003) 327341.
[16] G.A. Reichard, O.E. Owen, A.C. Haff, P. Paul, W.M. Bortz,
Ketone-body production and oxidation in fasting obese humans,
J. Clin. Invest. 53 (2) (1974) 508515.
[17] R.L. Leino, D.Z. Gerhart, R. Duelli, B.E. Enerson, L.R. Drewes,
Diet-induced ketosis increases monocarboxylate transporter
(MCT1) levels in rat brain, Neurochem. Int. 38 (6) (2001)
519527.
[18] B. Chance, H. Sies, A. Boveris, Hydroperoxide metabolism in
mammalian organs, Physiol. Rev. 59 (3) (1979) 527605.
[19] R.L. Veech, L.V. Eggleston, H.A. Krebs, The redox state of free
nicotinamide-adenine dinucleotide phosphate in the cytoplasm of
rat liver, Biochem. J. 115 (1969) 609619.
[20] R.L. Veech, B. Chance, Y. Kashiwaya, H.A. Lardy, G.F. Cahill
Jr., Ketone bodies, potential therapeutic uses, IUBMB Life 51 (4)
(2001) 241247.
[21] J.M. Freeman, E.P.G. Vining, Intractable epilepsy, Epilepsia 33
(1992) 11321136.
[22] S.L. Kinsman, E.P. Vining, S.A. Quaskey, D. Mellits, J.M.
Freeman, Efcacy of the ketogenic diet for intractable
ARTICLE IN PRESS
318
[23]
[24]
[25]
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
R.L. Veech / Prostaglandins, Leukotrienes and Essential Fatty Acids 70 (2004) 309319
seizure disorders: review of 58 cases, Epilepsia 33 (6) (1992)
11321136.
D.L. Gilbert, P.L. Pyzik, J.M. Freeman, The ketogenic diet:
seizure control correlates better with serum beta-hydroxybutyrate
than with urine ketones, J. Child Neurol. 15 (12) (2000) 787790.
M. Erecinska, D. Nelson, Y. Daikhin, M. Yudkoff, Regulation of
GABA level in rat brain synaptosomes: uxes through enzymes of
the GABA shunt and effects of glutamate, calcium, and ketone
bodies, J. Neurochem. 67 (6) (1996) 23252334.
M. Yudkoff, Y. Daikhin, I. Nissim, R. Grunstein, Effects of
ketone bodies on astrocyte amino acid metabolism, J. Neurochem. 69 (2) (1997) 682692.
A.E. Greene, M.T. Todorova, R. McGowan, T.N. Seyfried,
Caloric restriction inhibits seizure susceptibility in epileptic
EL mice by reducing blood glucose, Epilepsia 42 (11) (2001)
13711378.
R.L. Veech, Y. Kashiwaya, D.N. Gates, M.T. King, K. Clarke,
The energetics of ion distribution: the origin of the resting electric
potential of cells, IUBMB Life 54 (2002) 241252.
P.R. Huttenlocher, A.J. Wilbourn, J.M. Signore, Medium-chain
triglycerides as a therapy for intractable childhood epilepsy,
Neurology 21 (11) (1971) 10971103.
C.A. Dell, S.S. Likhodii, K. Musa, M.A. Ryan, W.M. Burnham,
S.C. Cunnane, Lipid and fatty acid proles in rats consuming
different high-fat ketogenic diets, Lipids 36 (4) (2001) 373378.
T.H. Best, D.N. Franz, D.L. Gilbert, D.P. Nelson, M.R. Epstein,
Cardiac complications in pediatric patients on the ketogenic diet,
Neurology 54 (12) (2000) 23282330.
S. Kielb, H.P. Koo, D.A. Bloom, G.J. Faerber, Nephrolithiasis
associated with the ketogenic diet, J. Urol. 164 (2) (2000) 464466.
G. Taubes, What if its all been a Big Fat Lie? Sect. Magazine, NY
Times, 2002.
E.C. Westman, W.S. Yancy, J.S. Edman, K.F. Tomlin, C.E.
Perkins, Effect of 6-month adherence to a very low carbohydrate
diet program, Am. J. Med. 113 (1) (2002) 3036.
S.A. Beck, M.J. Tisdale, Nitrogen excretion in cancer cachexia
and its modication by a high fat diet in mice, Cancer Res. 49 (14)
(1989) 38003804.
L.C. Nebeling, E. Lerner, Implementing a ketogenic diet based on
medium-chain triglyceride oil in pediatric patients with cancer, J.
Am. Diet. Assoc. 95 (6) (1995) 693697.
L.C. Nebeling, F. Miraldi, S.B. Shurin, E. Lerner, Effects of a
ketogenic diet on tumor metabolism and nutritional status in
pediatric oncology patients: two case reports, J. Am. Coll. Nutr.
14 (2) (1995) 202208.
P. Mukherjee, M.M. El Abbadi, J.L. Kasperzyk, M.K. Ranes,
T.N. Seyfried, Dietary restriction reduces angiogenesis and
growth in an orthotopic mouse brain tumour model, Br. J.
Cancer 86 (10) (2002) 16151621.
R.L. Veech, The toxic impact of parenteral solutions on the
metabolism of cells: a hypothesis for physiological parenteral
therapy, Am. J. Clin. Nutr. 44 (1986) 519551.
Fluid Resuscitation: State of the Science for Treating Combat
Casualties and Civilian Injuries, National Academy Press,
Washington DC, 1999.
H.B. Alam, B. Austin, E. Koustova, P. Rhee, Resuscitationinduced pulmonary apoptosis and intracellular adhesion molecule-1 expression in rats are attenuated by the use of Ketone
Ringers solution, J. Am. Coll. Surg. 193 (3) (2001) 255263.
L. Chan, J. Slater, J. Hasbargen, D.N. Herndon, R.L. Veech, S.
Wolf, Neurocardiac toxicity of racemic d,l-lactate uids, Integr.
Physiol. Behav. Sci. 29 (1994) 383394.
J.L. Van Hove, S. Grunewald, J. Jaeken, P. Demaerel, P.E.
Declercq, P. Bourdoux, et al., d,l-3-hydroxybutyrate treatment
of multiple acyl-CoA dehydrogenase deciency (MADD), Lancet
361 (9367) (2003) 14331435.
ARTICLE IN PRESS
R.L. Veech / Prostaglandins, Leukotrienes and Essential Fatty Acids 70 (2004) 309319
[61] J.D. Adams Jr., L.K. Klaidman, A.C. Leung, MPP+ and
MPDP+ induced oxygen radical formation with mitochondrial
enzymes, Free Radic. Biol. Med. 5 (2) (1993) 181186.
[62] Y. Kashiwaya, T. Takeshima, N. Mori, K. Nakashima, K.
Clarke, R.L. Veech, d-beta-hydroxybutyrate protects neurons in
models of Alzheimers and Parkinsons disease, Proc. Natl. Acad.
Sci. USA 97 (10) (2000) 54405444.
[63] D.A. Evans, H.H. Funkenstein, M.S. Albert, P.A. Scherr, N.R.
Cook, M.J. Chown, et al., Prevalence of Alzheimers disease in a
community population of older persons. Higher than previously
reported [see comments], J. Am. Med. Assoc. 262 (18) (1989)
25512556.
[64] R.N. Kalaria, S.U. Bhatti, E.A. Palatinsky, D.H. Pennington,
E.R. Shelton, H.W. Chan, et al., Accumulation of the beta
amyloid precursor protein at sites of ischemic injury in rat brain,
Neuroreport 4 (2) (1993) 211214.
[65] G. Kanayama, M. Takeda, H. Niigawa, Y. Ikura, H. Tamii, N.
Taniguchi, et al., The effects of repetitive mild brain injury on
cytoskeletal protein and behavior, Methods Find. Exp. Clin.
Pharmacol. 18 (2) (1996) 105115.
[66] S. Seshadri, A. Beiser, J. Selhub, P.F. Jacques, I.H. Rosenberg,
R.B. DAgostino, et al., Plasma homocysteine as a risk factor for
dementia and Alzheimers disease, N. Engl. J. Med. 346 (7) (2002)
476483.
[67] J. Kuusisto, K. Koivisto, L. Mykkanen, F.L. Helkala, M.
Vanhunen, K. Kervinen, et al., Association between features of
the insulin resistance syndrome and Alzheimers disease independently of apolipoprotein E4 phenotype: cross sectional population
based study, Brit. Med. J. 315 (1997) 10451049.
[68] D. Gabuzda, J. Busciglio, L.B. Chen, P. Matsudaira, B.A.
Yankner, Inhibition of energy metabolism alters the processing
of amyloid precursor protein and induces a potentially amyloidogenic derivative, J. Biol. Chem. 269 (1994) 1362313628.
319