Moderate grade hyperammonemia activates lactate dehydrogenase-4 and 6-phosphofructo-2-kinase to support increased lactate turnover in the brain slices

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.