Lysosomal cholesterol overload in macrophages promotes liver fibrosis in a mouse model of NASH

 The research group has revealed a novel pathological mechanism that cholesterol accumulation in macrophages promotes liver fibrosis in the development of non-alcoholic steatohepatitis (NASH). Along with the global increase in obesity, one in four individuals develops fatty liver, and 10-30% of them progress to NASH characterized by chronic inflammation and fibrosis.
Much attention has been paid to NASH because it is recognized as a leading cause of hepatocellular carcinoma, whereas there are no approved therapeutic strategies for NASH. The concept of ‘lipotoxicity’ has been pointed out that cytotoxic lipids, such as cholesterol, may directly cause cell death or act in a proinflammatory and profibrotic manner in the pathogenesis of NASH. This study demonstrated that cholesterol overload triggers phenotypic changes and profibrotic activation of macrophages interacting with dead hepatocytes.
Furthermore, we successfully synthesized a novel supramolecular β-cyclodextrin polyrotaxane (βCD-PRX) that promotes excretion of lysosomal cholesterol within macrophages, and revealed that βCD-PRX effectively ameliorates in NASH mouse models (conceptual diagram).

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