ArticleThe Journal of experimental medicine2023
Lysosomal cholesterol overload in macrophages promotes liver fibrosis in a mouse model of NASH.
Article in The Journal of experimental medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers, 1 of them a synthesis that pooled it.
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Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it.
- The Green Path to Liver Health: Herbal Solutions for Non-alcoholic Steatohepatitis.Cardiovascular & hematological disorders drug targets · 2025Pooled it
- Review
- Review
- Reprogramming macrophages to treat liver diseases.Hepatology (Baltimore, Md.) · 2026Review
- Annexin A2 Is Associated with Dietary Cholesterol-Induced Metabolic Dysregulation and the Progression of Hepatic Fibrosis.Metabolites · 2026Article
- Balancing cholesterol metabolism in the liver and gut: perspectives in health and disease.Nature reviews. Gastroenterology & hepatology · 2026Review
- The fatty liver index exhibits a dual association with chronic obstructive pulmonary disease: a machine learning-based analysis of two independent cohorts.Frontiers in nutrition · 2026Article
- Lipid metabolism-MAFLD crosstalk: mechanisms and therapy.Frontiers in endocrinology · 2026Review
- Single-cell transcriptome analyses reveal disturbed decidual microenvironment in women of advanced maternal age.Clinical and translational medicine · 2025Article
- Loss of LCAT function aggravates metabolic-associated steatohepatitis (MASH) in golden Syrian hamster.Clinical science (London, England : 1979) · 2025Article
- Immunopathogenic mechanisms and immunoregulatory therapies in MASLD.Cellular & molecular immunology · 2025Review
- Myeloid cells in chronic liver inflammation.Cellular & molecular immunology · 2025Review
- Microglial replacement in a Sandhoff disease mouse model reveals myeloid-derived β-hexosaminidase is necessary for neuronal health.Nature communications · 2025Article
- Metabolic Dysfunction-Associated Steatotic Liver Disease: A Silent Driver of Cardiovascular Risk and a New Target for Intervention.International journal of molecular sciences · 2025Review
- Transient Dietary Intervention Induces Healthy Adipose Tissue Expansion and Metabolically Healthy Obesity in Mice.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Novel Cell-to-Cell Communications Between Macrophages and Fibroblasts Regulate Obesity-Induced Adipose Tissue Fibrosis.Diabetes · 2025Article
- Location, location, location: Cholesterol in lipid droplets as a driver of MASH progression.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Deficiency of myeloid NPC1 exacerbates liver injury and fibrosis by impairing macrophage efferocytosis.Journal of advanced research · 2025Article
- Liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction-associated steatohepatitis.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Cholesterol crystals in the pathogenesis of atherosclerosis.Nature reviews. Cardiology · 2025Review
Corrections and comments
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Authors and funding
20 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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