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

Yevgeniya I Shurubor; Andrey B Krasnikov; Elena P Isakova; Yulia I Deryabina; Vladimir S Yudin; Anton A Keskinov; Boris F Krasnikov

doi:10.3390/biom14020217

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

Biomolecules. 2024 Feb 12;14(2):217. doi: 10.3390/biom14020217.

Authors

Yevgeniya I Shurubor¹, Andrey B Krasnikov², Elena P Isakova³, Yulia I Deryabina³, Vladimir S Yudin¹, Anton A Keskinov¹, Boris F Krasnikov^{1

4}

Affiliations

¹ Centre for Strategic Planning of FMBA of Russia, Pogodinskaya St., Bld. 10, 119121 Moscow, Russia.
² Independent Researcher, 24 Ivana Babushkina St., 117292 Moscow, Russia.
³ Bach Institute of Biochemistry, Research Center of Biotechnology of the Russian Academy of Sciences, 119071 Moscow, Russia.
⁴ Department of Biochemistry and Molecular Biology, Faculty of Medicine, N.I. Pirogov Russian National Research Medical University, 1 Ostrovitianova Str., 117997 Moscow, Russia.

Abstract

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 α-ketoglutarate (αKG) and α-ketoglutaramate (αKGM), as well as the enzymes associated with them, ω-amidase (ωA) 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 ~45%, the weight of the kidneys up to 5%, the brain up to ~20%, and the weight of the liver increased up to ~20%. The analysis revealed: (i) a decrease in the activity of ωA and GTK in the tissues of the brain, kidneys, and liver of rats with chronic HE (by ~3, 40, and 65% and ~10, 60, and 70%, respectively); and (ii) the appearance of a significant imbalance in the content of metabolites of the Gln-Glu cycle, αKG, and αKGM. It is indicative that a ~1.5-12-fold increase in the level of αKG in the blood plasma and tissues of the organs of rats with chronic HE was accompanied by a synchronous, ~1.2-2.5-fold decrease in the level of αKGM. 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 αKG/αKGM ratio, which can act as a potential marker for diagnosing the degree of HE development.

Keywords: HPLC; glutamine transaminase; hepatoencephalopathy; thioacetamide; tricarboxylic acid cycle; α-ketoglutaramate; α-ketoglutarate; ω-amidase.

MeSH terms

Animals
Glutamic Acid / metabolism
Glutamine* / metabolism
Humans
Ketoglutaric Acids* / metabolism
Liver / metabolism
Rats

Substances

alpha-ketoglutaramate
Ketoglutaric Acids
Glutamine
Glutamic Acid

Grants and funding

This research was funded in part by the Russian Ministry of Science and Education, grant number 14.604.21.0116, awarded to B.F.K. The unique identification number of the applied scientific research was RFMEFI60414X0116, and through base funding from the Ministry of Science and Higher Education of the Russian Federation (E.P.I. and Y.I.D.).