RESUMEN
The minipig can serve as a good pharmacological model for human subjects. However, the long-term pathogenesis of high-calorie diet-induced metabolic syndromes, including NASH, has not been well described in minipigs. We examined the development of metabolic syndromes in Bama minipigs that were fed a high-fat, high-sucrose diet (HFHSD) for 23 months, by using histology and serum biochemistry and by profiling the gene expression patterns in the livers of HFHSD pigs compared to controls. The pathology findings revealed microvesicular steatosis, iron overload, arachidonic acid synthesis, lipid peroxidation, reduced antioxidant capacity, increased cellular damage, and inflammation in the liver. RNA-seq analysis revealed that 164 genes were differentially expressed between the livers of the HFHSD and control groups. The pathogenesis of early-stage NASH was characterized by hyperinsulinemia and by de novo synthesis of fatty acids and nascent triglycerides, which were deposited as lipid droplets in hepatocytes. Hyperinsulinemia shifted the energy supply from glucose to ketone bodies, and the high ketone body concentration induced the overexpression of cytochrome P450 2E1 (CYP2E1). The iron overload, CYP2E1 and alcohol dehydrogenase 4 overexpression promoted reactive oxygen species (ROS) production, which resulted in arachidonic and linoleic acid peroxidation and, in turn, led to malondialdehyde production and a cellular response to ROS-mediated DNA damage.
Asunto(s)
Glucosa/metabolismo , Hiperinsulinismo/complicaciones , Hiperinsulinismo/metabolismo , Cuerpos Cetónicos/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Animales , Antioxidantes/metabolismo , Peso Corporal , Colesterol/sangre , Colesterol/metabolismo , Daño del ADN , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Ácidos Grasos/metabolismo , Fibrosis , Perfilación de la Expresión Génica , Hepatocitos/metabolismo , Hepatocitos/patología , Hepatocitos/ultraestructura , Hiperplasia , Resistencia a la Insulina , Islotes Pancreáticos/metabolismo , Islotes Pancreáticos/patología , Metabolismo de los Lípidos , Peroxidación de Lípido , Hígado/metabolismo , Hígado/patología , Enfermedad del Hígado Graso no Alcohólico/patología , Estrés Oxidativo , Fenotipo , Porcinos , Transcriptoma , Triglicéridos/sangre , Triglicéridos/metabolismoRESUMEN
OBJECTIVES: The effect of a long-term high-fat, high-caloric diet on the dysfunction of pancreas has not been clarified. We investigated the pancreatic histopathology and ß-cell apoptosis in Bama minipigs after 23 months on a high-fat high-sucrose diet (HFHSD). METHODS: Bama minipigs were randomly assigned to control (n = 6) and HFHSD groups (n = 6) for 23 months, and biochemical parameters were measured. Pancreata were subjected to histological analysis, followed by assessment with transmission electron microscopy. Lipid peroxidation was determined by the malondialdehyde concentration and antioxidant enzyme activity. Β-cell apoptosis was measured by an immunohistochemical method. RESULTS: In the HFHSD group, the islets were enlarged, and the pancreatic tissue had observed significant fatty infiltration. Moreover, the feeding program damaged the normal pancreatic tissue structure. The level of lipid peroxidation was increased, and the activities of pancreatic antioxidant enzymes were significantly decreased. The expression levels of caspase-3, Bax, and insulin were significantly increased (P < 0.05), and the expression levels of proliferating cell nuclear antigen and Bcl-2 were decreased (P < 0.05). CONCLUSIONS: The long-term HFHSD promotes pancreatic steatosis and oxidative stress, which increases ß-cell apoptosis as indicated by the activation of caspase-3 through the mitochondrial pathway (Bcl-2/Bax).