Structural Features of the Liver of Leptin-Resistant db/db Mice with Systematic Administration of Recombinant Apolipoprotein A-I

The aim was to establish the nature of liver remodeling in hyperglycemia and insulin resistance in leptin-resistant db/db mice and to study the possibility of reversing the identified structural changes during glucose metabolism correction using systematic administration of recombinant apolipoprotein A-I (rApoA-I). Material and methods. The structural organization of the liver was studied in db/db mice (n=46) at the age of 10, 12 and 24 weeks, including weekly subcutaneous administration of rApoA-I (at a dose of 7 mg/kg body weight) as a glucose metabolism corrector from the age of 8 weeks. C57/Bl mice without glucose metabolism disorders (n=12) were used as a control. Liver samples for microscopical examination were fixed in 10% neutral formalin, embedded in paraffin and stained with hematoxylin and eosin, according to Mallory, and the PAS reaction was performed. To obtain semi-thin sections, liver fragments were fixed in 4% paraformaldehyde, post-fixed in 1% osmium tetroxide, embedded in a mixture of epon and araldite. Semi-thin sections stained with azure II were used for stereological analysis. Results. In 24-week-old db/db mice, glucose and insulin concentrations were increased (by 2.9 and 6.5 times, respectively, p<0.001) compared to the age-matched control, which reflected glucose metabolism disorders. Systematic administration of rApoA-I starting from the age of 8 weeks resulted in a reliable decrease in the concentration of glucose in the blood plasma (by 37%) in mice at the age of 24 weeks, however, this index remained elevated (2 times) relative to the control animals. Administration of rApoA-I did not affect the concentration of insulin throughout the experiment. The peculiarities of the structural organization of the liver of db/db mice include pronounced discomplexation of the liver lobules with pronounced dystrophic/necrobiotic changes in hepatocytes, a significant decrease in the volume densities of hepatocyte nuclei, sinusoids and connective tissue components when compared with mice with normal indices of glucose metabolism. The most significant characteristics of the morphological picture of the liver of db/db mice include massive necrotic lesions of hepatocytes, sometimes affecting the entire lobule in the absence of leukocyte infiltration. Systematic administration of rApoA-I did not significantly affect the nature of liver remodeling, but contributed to a decrease in the severity of dystrophic damage of hepatocytes and a decrease in necrotic foci. Conclusion. The data obtained indicate that systematic administration of rApoA-I does not change the nature of liver remodeling in db/db mice with genetically determined leptin resistance, despite a decrease in plasma glucose levels, but a decrease in the severity of pathological changes is noted, in particular, a decrease in the volume density of hepatocyte necrosis foci and a less pronounced decrease in the volume density of sinusoids and the volume ratio of sinusoids to hepatocytes.

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