Energy Metabolites and Indicative Significance of -Ketoglutarate and -Ketoglutaramate in Assessing the Progression of Chronic Hepatoencephalopathy

In the example of a rat model with chronic hepatoencephalopathy (HE), changes in the organ morphology of rats affect the balance of metabolites of the tricarboxylic acid (TCA) cycle and metabolites of the glutamine-glutamate (Gln-Glu) cycle, namely alpha-ketoglutarate (alpha KG) and alpha-ketoglutaramate (alpha KGM), as well as the enzymes associated with them, omega-amidase (omega A) and glutamine transaminase (GTK). This model of rats was obtained as a result of 2-22 weeks of consumption by animals of hepatotoxin thioacetamide (TAA) added to drinking water at a concentration of 0.4 g/L. The control (n = 26) and TAA-induced (n = 55) groups of rats consisted of 11 cohorts each. The control cohorts consisted of 2-4 rats, and the TAA-induced cohorts consisted of 4-7 individuals. Every two weeks, samples of blood plasma, liver, kidney, and brain tissues were taken from the next cohort of rats (a total of 320 samples). By the end of the experiment, irreversible morphological changes were observed in the organs of rats: the weight of the animals was reduced up to similar to 45%, the weight of the kidneys up to 5%, the brain up to similar to 20%, and the weight of the liver increased up to similar to 20%. The analysis revealed: (i) a decrease in the activity of omega A and GTK in the tissues of the brain, kidneys, and liver of rats with chronic HE (by similar to 3, 40, and 65% and similar to 10, 60, and 70%, respectively); and (ii) the appearance of a significant imbalance in the content of metabolites of the Gln-Glu cycle, alpha KG, and alpha KGM. It is indicative that a similar to 1.5-12-fold increase in the level of alpha KG in the blood plasma and tissues of the organs of rats with chronic HE was accompanied by a synchronous, similar to 1.2-2.5-fold decrease in the level of alpha KGM. The data obtained indicate an essential involvement of the Gln-Glu cycle in the regulation of energy metabolism in rats under conditions of chronic HE. Attention is focused on the significance of the alpha KG/alpha KGM ratio, which can act as a potential marker for diagnosing the degree of HE development.