Abstract
Obesity and diabetes mellitus are known to lead to the development of metabolic syndrome and non-alcoholic fatty liver disease (NAFLD). The mechanisms of programmed cell death are actively involved in maintaining cellular homeostasis along development of NAFLD. Proteins of the BCL-2 family are key regulators of physiological and pathological apoptosis. Homozygous males of BKS.Cg-Dock7mLeprdb/+/+/J mice (db/db mice) are characterized by progressive obesity and the development of type 2 diabetes mellitus (DM2) with severe hyperglycemia at 4–8 weeks and organ lesions at 8–10 weeks of age. The aim of this research was to study the expression of molecular cell regulators of apoptosis in liver cells of db/db mice males at different stages of obesity and diabetes development (at the age of 10 and 18 weeks). Immunohistochemical analysis (using the indirect avidin-biotin peroxidase method) and morphometric evaluation of the expression of the antiapoptotic protein Bcl-2 and the proapoptotic protein Bad in liver cells of studied animals at different stages of obesity and DM2 were carried out. An excess of the value of the Bcl-2 protein staining area over the Bad protein staining area was revealed in the liver of 10-week-old animals. The Bcl-2/Bad expression area ratio in 10-week-old animals was twice as high as in 18-week-old animals, which indicates the presence of conditions for blocking apoptosis in the liver of younger db/ db mice. At the 18th week of life, db/db mice displayed an almost threefold increase in the expression area of the Bad protein against the background of an unchanged expression of the Bcl-2 protein. The decrease in the Bcl-2/Bad staining area ratio in 18-week-old animals was due to the increase in the Bad expression area, which indicates the absence of antiapoptotic cell protection and creates conditions for activation of the mitochondrial pathway of apoptosis in the liver of male db/db mice with pronounced signs of obesity and DM2.
Highlights
Mechanisms of programmed cell death are actively involved in maintaining cell homeostasis in the development of nonalcoholic fatty liver disease (NAFLD) (Schuppan, Schattenberg, 2013)
Recent data indicate that obesity and diabetes lead to the development of metabolic syndrome and NAFLD, which can progress in patients with this disease to non-alcoholic steatohepatitis, which includes the risk of cirrhosis and hepatocellular carcinoma (Shimizu et al, 2011)
We have previously identified ultrastructural disorders of the energy and protein-synthesis apparatus in liver cells, carbohydrate and fat metabolism disturbances in the liver of 18-week-old male db/db mice with DM2, which leads to the development of protein and fat dystrophy in hepatocytes (Michurina et al, 2016b)
Summary
Mechanisms of programmed cell death are actively involved in maintaining cell homeostasis in the development of nonalcoholic fatty liver disease (NAFLD) (Schuppan, Schattenberg, 2013). Recent data indicate that obesity and diabetes lead to the development of metabolic syndrome and NAFLD, which can progress in patients with this disease to non-alcoholic steatohepatitis, which includes the risk of cirrhosis and hepatocellular carcinoma (Shimizu et al, 2011). Proteins of the BCL-2 family are key regulators of physiological and pathological apoptosis. Molecular features of the development of the mitochondrial pathway of apoptosis in the liver of male db/db mice in postnatal ontogenesis at different development stages of obesity and type 2 diabetes mellitus (DM2) have not yet been studied
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