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

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

Yevgeniya I Shurubor  1 , Andrey B Krasnikov  2 , Elena P Isakova  3 , Yulia I Deryabina  3 , Vladimir S Yudin  1 , Anton A Keskinov  1 , Boris F Krasnikov  1   4
Affiliations

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

Yevgeniya I Shurubor et al. Biomolecules. .

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.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The appearance of the abdominal cavity (A), liver (B), kidneys (C), and brain (D) of the control (1) and TAA-induced group (2) animals at the 20th week of the experiment.
Figure 2
Figure 2
Liver sections of control (A) and TAA-induced (B–D) rats 4 weeks after the initiation of the TAA aqueous solution. Panel (B): small droplet fatty degeneration is indicated by arrows. Panel (C): the arrows indicate diapedetic hemorrhages. Panel (D): the arrow indicates the foci of small-cell formations. The tissues were stained with hematoxylin–eosin; magnification: ×400.
Figure 3
Figure 3
Kidney tissue sections of control (A) and TAA-induced (B) rats after 4 weeks of taking an aqueous solution of TAA. Tissues were stained with hematoxylin–eosin; ×400 magnification.
Figure 4
Figure 4
Brain tissue sections of control (A) and TAA-induced (B) rats after 4 weeks of taking an aqueous solution of TAA. Tissues were stained with hematoxylin–eosin; ×400 magnification.
Figure 5
Figure 5
Specific activity (nmols/mg of wet tissue/min) of ωA (A) and GTK (B) in liver and kidney tissues of control (black circles) and TAA-induced (red triangles) rats. The data are presented as average values (for the period of 2–22 weeks).
Figure 6
Figure 6
Plasma levels of pyruvate, α-ketoglutarate, and α-ketoglutaramate in the control (black circles) and TAA-induced groups of rats (red triangles). Data are presented for the statistically significant metabolites as average values over a period of 2–22 weeks.
Figure 7
Figure 7
Levels of pyruvate and fumarate in the liver tissues of the control (black circles) and TAA-induced groups of rats (red circles). Data are presented for the statistically significant metabolites as average values over a period of 2–22 weeks.
Figure 8
Figure 8
Levels of α-ketoglutaramate in the kidney tissues of the control (black circles) and TAA-induced groups of rats (red triangles). Data are presented for the statistically significant metabolites as average values over a period of 2–22 weeks.
Figure 9
Figure 9
Formate levels in the brain tissues of the control (black circles) and TAA-induced groups of rats (red triangles). Data are presented for the statistically significant metabolites as mean values over a period of 2–22 weeks.
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