Accumulation of lipotoxic
lipids, such as free
cholesterol, induces hepatocyte death and subsequent
inflammation and
fibrosis in the pathogenesis of
nonalcoholic steatohepatitis (NASH). However, the underlying mechanisms remain unclear. We have previously reported that hepatocyte death locally induces phenotypic changes in the macrophages surrounding the
corpse and remnant
lipids, thereby promoting
liver fibrosis in a murine model of NASH. Here, we demonstrated that lysosomal
cholesterol overload triggers lysosomal dysfunction and profibrotic activation of macrophages during the development of NASH. β-
cyclodextrin polyrotaxane (βCD-PRX), a unique supramolecule, is designed to elicit free
cholesterol from lysosomes. Treatment with βCD-PRX ameliorated
cholesterol accumulation and profibrotic activation of macrophages surrounding dead hepatocytes with
cholesterol crystals, thereby suppressing
liver fibrosis in a NASH model, without affecting the hepatic
cholesterol levels. In vitro experiments revealed that
cholesterol-induced lysosomal stress triggered profibrotic activation in macrophages predisposed to the steatotic microenvironment. This study provides evidence that dysregulated
cholesterol metabolism in macrophages would be a novel mechanism of NASH.