Insulin Resistance and Oxidative Stress Determines Destiny of Kupffer Cells by Induces Lipophagy Activity, Polarization and Isolation by Capillarization of Sinusoids in an Animal Model of Liver Metabolic Disease: Psammomys obesus
摘要
The activity of Kupffer cells is complex and not fully understood. For follow the fate of these cells, we analyzed their ultrastructural characteristics and morphological changes in the pathogenesis of metabolic liver disease; we utilized an animal model of insulin resistance, Psammomys obesus, induced by a high-calorie diet over nine months. This diet induced metabolic syndrome and impaired glutathione synthesis by increasing reactive oxygen species production. Electron microscopy revealed a dynamic interaction between hepatocytes-Kupffer cells during the steatosis stage. Excess circulating lipids are eliminated through lipophagy, a process involving the formation of lipophagic vacuoles derived from the membranes of the rough endoplasmic reticulum of Kupffer cells. Subsequently, these cells exhibited phenotypic polarization, with one membrane face in contact with the injured hepatocyte membrane and the opposite face intimately linked to a monocyte membrane; this is the site of inflammatory cell recruitment. Persistent nutritional stress induces loss of sinusoidal endothelium fenestration through the formation of a basal lamina and capillarization of sinusoids, accordingly, loses contact Kupffer cells—hepatocytes. In parallel, the phenotypic changes in Kupffer cells were correlated with the expression of the macrophage scavenger receptor cd163, which increased as the disease progressed from steatosis to steatohepatitis and decreased in the fibrosis stage. Kupffer cells represent a therapeutic target for the treatment of steatosis and its progression. Psammomys obesus serves as an excellent animal model that replicates this disease in humans and provides a valuable in vivo approach to study cellular and molecular evolution, which is otherwise inaccessible in human subjects.