Role of chronic inflammation in the pathogenesis of nonalcoholic steatohepatitis: lessons from a unique mouse model using melanocortin receptor-deficient mice

[摘要] Nonalcoholic fatty liver disease (NAFLD) is a clinical spectrum that encompasses simple steatosis to nonalcoholic steatohepatitis (NASH), the latter of which is characterized by chronic inflammation and fibrosis. NASH is now becoming the leading cause of cirrhosis and hepatocellular carcinoma worldwide. The pathophysiology of NASH is multifactorial and, therefore, not yet completely understood, although it is pointed out that hepatocyte death and subsequent inflammation play a central roles in disease pathogenesis. Since stromal cells dramatically change their cellular components and activation status as liver fibrosis develops, it is important to reveal the subset responsible for the disease development in each etiology. Macrophages foam crown-like structures (CLS), in which CD11c-positive macrophages surround dead hepatocytes induced by lipotoxic injury in mouse and human NASH. Hepatic CLS-constituting macrophages exhibit gene expression profiles distinct from other scattered macrophages in the liver, suggesting NASH-specific macrophages represent a subset that drives metabolic stress-induced liver fibrosis. Moreover, cancer-associated pathways are upregulated in activated fibroblasts from the liver of a mouse NASH model, suggesting that fibroblasts provide the microenvironment that promotes tumor progression. A better understanding of the upstream signals and regulatory mechanisms that drive the generation of NASH-specific macrophage and fibroblast subsets is crucial for the development of novel diagnostic and therapeutic strategies.

[学科分类] 内分泌与代谢学

[关键词] Chronic inflammation;Macrophages;Fibroblasts;Cell death;Crown-like structure