RESUMEN
By using a unique animal model of type 2 diabetes mellitus, Psammomys obesus induced by a high-calorie diet (HCD) for nine months, we showed for the first time, in the liver, the impact of inflammation on the remodeling of intercellular junction molecules E-cadherins during the progression of steatohepatitis. Under the effect of HCD, the expressions of immunohistochemical markers, Tumor Necrosis Factor alpha (TNFα) and E-cadherins were inversely correlated. Ultrastructural examination revealed the involvement of destabilization and loss of E-cadherins in the process of hepatic pathogenesis. This mechanical maintenance stress was favored by the recruitment of immune cells which contributed to the triggering and progression of fibrosis by the enlargement of the intercellular space and the invasion of collagen fibers. Furthermore to escape cell death, loss of E-cadherins played a major role in mediating fibrosis. Psammomys obesus is a promising model for experimental research, enabling the extrapolation of observed structural and functional alterations in humans, the objective to find new therapeutic targets. The physiological resemblance between Psammomys obesus and humans enhances the precision and relevance of biomedical research efforts.
Asunto(s)
Cadherinas , Diabetes Mellitus Tipo 2 , Modelos Animales de Enfermedad , Gerbillinae , Hígado , Factor de Necrosis Tumoral alfa , Animales , Factor de Necrosis Tumoral alfa/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patología , Cadherinas/metabolismo , Hígado/metabolismo , Hígado/patología , Hígado/ultraestructura , Enfermedades Metabólicas/patología , Enfermedades Metabólicas/metabolismo , MasculinoRESUMEN
The aim of this study was to reveal the effects of obesity and phytotherapy with 20-hydroxyecdysone (20E) on the nuclei of adrenal zona fasciculata (ZF) in the gerbil Gerbillus tarabuli by analyzing nuclear shape and gray-level co-occurrence matrix (GLCM) texture characteristics and by quantifying heterochromatin. Twelve gerbils were divided into three groups: control (C), HC and HC-20E (animals receiving a high-calorie-diet without or with a supplement of 20E, respectively). The adrenals were removed and fixed for histological and statistical analysis. Principal component analysis showed a positive correlation of area, perimeter and textural correlation in C. Nevertheless, a negative correlation was recorded for contrast and entropy. The obesity caused a disorder in nuclear texture; negative correlation was noted with heterochromatin fraction, which may be related to increased ZF activity. However, administration of 20E seems to improve the nuclear state by preserving circularity, uniformity and homogeneity of nuclei as well as the proportion of heterochromatin, which could be a sign of a downregulation of cell activity.Our results suggest that new techniques of image processing could contribute to the understanding of nuclear changes associated with obesity and its possible therapy in this gerbil model for metabolic syndrome.
Asunto(s)
Síndrome Metabólico , Zona Fascicular , Animales , Heterocromatina , Gerbillinae , Ecdisterona , ObesidadRESUMEN
The aim of this study was to show, for the first time, the effect of a hypercaloric diet on the mitochondrial reshuffle of hepatocytes during the progression from steatosis to steatohepatitis to cirrhosis in Psammomys obesus, a typical animal model of the metabolic syndrome. Metabolic and oxidative stresses were induced by feeding the animal through a standard laboratory diet (SD) for nine months. Metabolic parameters, liver malondialdehyde (MDA) and glutathione (GSH), were evaluated. The pathological evolution was examined by histopathology and immunohistochemistry, using CD3 and CD20 antibodies. The dynamics of the mitochondrial structure was followed by transmission electron microscopy. SD induced a steatosis in this animal that evolved under the effect of oxidative and metabolic stress by the appearance of adaptive inflammation and fibrosis leading the animal to the cirrhosis stage with serious hepatocyte damage by the triggering, at first the mitochondrial fusion-fission cycles, which attempted to maintain the mitochondria intact and functional, but the hepatocellular oxidative damage was increased inducing a vicious circle of mitochondrial alteration and dysfunction and their elimination by mitophagy. P. obesus is an excellent animal model of therapeutic research that targets mitochondrial dysfunction in the progression of steatosis.
Asunto(s)
Gerbillinae , Hiperfagia/metabolismo , Resistencia a la Insulina , Hígado/metabolismo , Mitocondrias Hepáticas/metabolismo , Infiltración Neutrófila , Estrés Oxidativo , Animales , Dieta , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Hígado Graso/metabolismo , Hígado Graso/patología , Glutatión/metabolismo , Hiperfagia/patología , Inflamación/metabolismo , Inflamación/patología , Hígado/patología , Masculino , Malondialdehído/metabolismo , Mitocondrias Hepáticas/patologíaRESUMEN
The aim of our transmission electron microscope study was to show, for the first time, the alteration of liver cells involved in the evolution of steatosis to steatohepatitis on a murine model of the diet-induced metabolic syndrome, Psammomys obesus. This pathologic evolution was induced by using the standard laboratory diet during 10 months, and analyzed with metabolic studies and the immunohistochemistry technique. Four months later, hepatocytes charged with lipid vacuoles were involved in autophagy. Furthermore, in the sinusoids, we observed Kupffer cells, neutrophils and macrophages. All those cells were associated with necrotic hepatocytes inducing hepatocellular necrosis. We also noticed a synthesis of extracellular matrix in excess, caused by proliferation and activation of hepatic stellate cells in necrotic areas. We observed as well a fragmentation of the endoplasmic reticulum, which formed isolated membranes (phagophores) surrounding mitochondria. The complex membrane-mitochondria formed like an autophagosome. Thus, a defect in autophagy favored the development and progression of steatohepatitis. In conclusion, our results suggest that P. obesus is very well adapted for experimental research, and could help improve the early therapeutic management of patients and the prevention of autophagic risks in the liver.