Genetically determined fatty liver disease and type 2 diabetes mellitus in db/db mice. The effect of melatonin on lipid metabolism in the liver, micro- and ultrastructural characteristics

Background. Obesity, diabetes mellitus and metabolic dysfunction-associated fatty liver disease are some of the most pressing issues of our time. Melatonin has been shown to be effective in correcting a number of metabolic disorders, but there is insufficient data on its effect on morphological features of lipid metabolism in obesity and type 2 diabetes mellitus.

The aim. To study micro- and ultrastructural features of lipid metabolism in the liver of db/db mice with obesity and type 2 diabetes mellitus and to evaluate the effects of melatonin treatment on them.

Methods. Female db/db mice from 8 weeks of age were administered melatonin solution intragastrically (1 mg/kg in 200 μl of water) for 56 days. The comparison groups were intact (control) and placebo animals, which were injected with 200 μl of  dH2O according to  the  above scheme. Light-optical and  electron microscopic examinations of liver samples were performed.

Results. In control and placebo db/db mice, hepatocytes were characterized by vacuolar dystrophy and aberrant accumulation of small lipid inclusions, sometimes with the presence of giant lipid droplets (LDs). Also we revealed: endoplasmic reticulum stress; densification of the mitochondrial matrix with chaotically arranged cristae, or destruction of their ultrastructure; mitophagosomes; complexes of mitochondria with LDs; mass exocytosis of  LDs into the  interhepatocyte slits and Dysse spaces with stagnation of intercellular fluid. Treatment with melatonin resulted in a decrease in the relative number of hepatocytes with LDs, a decrease in the percentage of cells with small-droplet inclusions, and  an  increase in  the  percentage of  hepatocytes with medium and large, but not giant LDs. The mitochondria ultrastructure improved, and  the  formation of  complexes from  mitochondria with  large compartments of granular endoplasmic reticulum increased. Exocytosis of LDs into the interhepatocytic slits was not detected.

Conclusion. Melatonin can be considered as a promising agent in complex therapy of metabolic associated fatty liver disease in obesity and type 2 diabetes mellitus.

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