Abstract
Rapid metabolism of lactate is an important aspect of bioenergetic adaptation in the brain during non-physiological conditions. The low grade hyperammonemia (HA) is a common condition in the patients with chronic hepatic encephalopathy (HE); however, biochemistry of lactate turnover during low grade HA remains poorly defined. The present article describes profile of lactate dehydrogenase (LDH) isozymes vis-a-vis lactate level in the brain slices exposed with 0.1–0.5 mM ammonia, found to exist in the brain during chronic HE. A significant increment in LDH activity coincided with a similar increase in lactate level in the brain slices exposed with 0.5 mM ammonia. This was consistent with a selective increment of LDH-4 that synthesizes lactate from pyruvate with a concomitant decline in LDH-1 which catalyzes conversion of lactate to pyruvate; resulting into ~3-fold increase in LDH-4/LDH-1 ratio in those brain slices. The PFK2 domain of PFK2/FBPase2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) regulates glycolysis to maintain the pyruvate pool for lactate synthesis. The PFK2 expression was also observed to be increased ~2-fold (P < 0.001) in 0.5 mM ammonia treated brain slices. These findings provide enzymatic regulation of increased lactate turnover in the brain exposed with moderate HA.
References
Roberts EL Jr (2007) The support of energy metabolism in the central nervous system with substrates other than glucose. In: Lajtha A, Gibson GE, Dienel GA (eds) Handbook of neurochemistry and molecular neurobiology, 3rd edn. Springer, Berlin, pp 139–179
Ross JM, Oberg J, Brene S, Coppotelli G, Terzioglu M, Pernold K, Goiny M, Sitnikov R, Kehr J, Trifunovic A, Larsson NG, Hoffer BJ, Olson L (2010) High brain lactate is a hallmark of aging and caused by a shift in the lactate dehydrogenase A/B ratio. Proc Natl Acad Sci USA 107:20087–20092
Hertz L, Kala G (2007) Energy metabolism in brain cells: effects of elevated ammonia concentrations. Metab Brain Dis 22:199–218
Zwingmann C, Chatauret N, Leibfritz D, Butterworth RF (2003) Selective increase of brain lactate synthesis in experimental acute liver failure: results of a [1H–13C] nuclear magnetic resonance study. Hepatology 37:420–428
Lockwood A, Weissenborn K, Butterworth RF (1997) An image of the brain in patients with liver disease. Curr Opin Neurol 10:525–533
Provent P, Kickler N, Barbier EL, Bergerot A, Farion R, Goury S, Marcaggi P, Segebarth C, Coles JA (2007) The ammonium induced increase in rat brain lactate concentration is rapid and reversible and is compatible with trafficking and signaling roles for ammonium. J Cereb Blood Flow Metab 27:1830–1840
Ventura F, Rosa JL, Ambrosio S, Pilkis SJ, Bartrons R (1992) Bovine brain 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Evidence for a neural-specific isozyme. J Biol Chem 267:17939–17943
Singh S, Trigun SK (2010) Activation of neuronal nitric oxide synthase in cerebellum of chronic hepatic encephalopathy rats is associated with up-regulation of NADPH-producing pathway. Cerebellum 9:384–397
Okar DA, Manzano A, Navarro-Sabate A, Riera L, Bartrons R, Lange AJ (2001) PFK-2/FBPase-2: maker and breaker of the essential biofactor fructose-2, 6-bisphosphate. Trends Biochem Sci 26:30–35
Kessler R, Bleichert F, Warnke JP, Eschrich K (2008) 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3) is up-regulated in high-grade astrocytomas. J Neurooncol 86:257–264
Mehrotra A, Trigun SK (2012) Moderate grade hyperammonemia induced concordant activation of antioxidant enzymes is associated with prevention of oxidative stress in the brain slices. Neurochem Res 37:171–181
Koiri RK, Trigun SK, Mishra L, Pandey K, Dixit D, Dubey SK (2009) Regression of Dalton’s lymphoma in vivo via decline in lactate dehydrogenase and induction of apoptosis by a ruthenium (II)-complex containing 4-carboxy-N ethylbenzamide as ligand. Invest New Drugs 27:503–516
Koiri RK, Trigun SK (2011) Dimethyl sulfoxide activates tumor necrosis factor α-p53 mediated apoptosis and downregulates d-fructose-6-phosphate-2-kinase and lactate dehydrogenase-5 in Dalton’s lymphoma in vivo. Leukemia Res 35:950–956
Wang T, Kass S (1997) Preparation of brain slices. In: Rayne RC (ed) Neurotransmitter methods. Humana, Totowa, pp 1–14
Felipo V, Butterworth RF (2002) Neurobiology of ammonia. Prog Neurobiol 67:259–279
Voet D, Voet JG (2011) Biochemistry. Wiley, New York
Ratnakumari L, Murthy CRK (1993) Response of rat cerebral glycolytic enzymes to hyperammonemic states. Neurosci Lett 161:37–40
Acknowledgments
Financial support to this work was provided by Department of Science & Technology project (No. SR/SO/AS-08/2007) to SKT. Award of SRF by Indian Council of Medical Research, New Delhi, to AM and the facilities due to UGC CAS programmes to Department of Zoology, BHU, are also acknowledged.
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The authors declare no conflict of interest with respect to this article.
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Mehrotra, A., Trigun, S.K. Moderate grade hyperammonemia activates lactate dehydrogenase-4 and 6-phosphofructo-2-kinase to support increased lactate turnover in the brain slices. Mol Cell Biochem 381, 157–161 (2013). https://doi.org/10.1007/s11010-013-1698-3
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DOI: https://doi.org/10.1007/s11010-013-1698-3