Apoptosis in the liver of male <em>db/db</em> mice during the development of obesity and type 2 diabetes

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-Dock7 m Lepr db /+/+/J mice (db/db mice) are charac terized 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 mo lecular 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.

Zinc Supplementation Prevented Type 2 Diabetes-Induced Liver Injury Mediated by the Nrf2-MT Antioxidative Pathway

“…Type 2 Diabetic Liver Depending on MT. Hepatic apoptosis is regarded as the cytological basis for type 2 diabetes-induced liver damage [32]. In the present study, the hepatic apoptosis was first evaluated by TNUEL staining, which showed that the positive apoptotic liver cells, displayed in red, were hardly These results suggested endogenous MT mediated the prevention of zinc treatment on type 2 diabetes-induced hepatic apoptosis.…”

“…Hepatic apoptosis is regarded as the cytological basis for type 2 diabetes-induced liver damage [ 32 ]. In the present study, the hepatic apoptosis was first evaluated by TNUEL staining, which showed that the positive apoptotic liver cells, displayed in red, were hardly observed in the nondiabetic mice (Figures 7(a) and 7(b) ).…”

miR-449a disturbs atherosclerotic plaque stability in streptozotocin and high-fat diet-induced diabetic mice by targeting CEACAM1

“…This results in a limitation of the model to fully mimic the complicated pathology development in DM-associated AS. Although previous studies have indicated that genetically obese rodent model db/db mice are more similar to T2DM [ 50 , 51 ], it is recognized, that STZ-induced ApoE −/− mice have shown more stable and recognized spontaneous atherosclerotic plaques [ 52 , 53 ]. Moreover, another limitation was that we constructed the HG-induced HUVECs to examine the function and mechanism of the miR-449a/CEACAM1 axis in vitro.…”

Obesity and Risk for Lymphoma: Possible Role of Leptin

“…Leptin has demonstrated the ability to inhibit apoptosis and induce cell cycle by elevating Bcl-2 and cyclin D1 in leptin-receptor-deficient ( db/db ) mice [ 188 ]. Similarly, the Bcl-2 protein expression was elevated in db/db mice with diabetes [ 189 , 190 , 191 ], Which may be predisposed to develop lymphoma [ 192 ]. This adipokine also decreased the apoptosis of myocardial cells in rats via bcl-2 [ 193 ] and reduced the apoptosis of beta cells at physiological concentrations in vitro by maintaining or up-regulating bcl-2 expression, which could promote non-insulin-dependent diabetes mellitus [ 194 , 195 ].…”