期刊
SCIENTIFIC REPORTS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-017-13058-z
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资金
- Maag Lever Darm Stichting (MLDS) [WO 08-16, WO 11-35]
- Netherlands Organisation for Scientific Research (NWO) [016.126.327]
- Netherlands Organisation for Scientific Research (NWO) (ASPASIA) [015.008.043]
Despite the consistent rise of non-alcoholic steatohepatitis (NASH) worldwide, the mechanisms that govern the inflammatory aspect of this disease remain unknown. Previous research showed an association between hepatic inflammation and lysosomal lipid accumulation in blood-derived hepatic macrophages. Additionally, in vitro findings indicated that lipids, specifically derived from the oxidized low-density lipoprotein (oxLDL) particle, are resistant to removal from lysosomes. On this basis, we investigated whether lysosomal lipid accumulation in blood-derived hepatic macrophages is causally linked to hepatic inflammation and assessed to what extent increasing anti-oxLDL IgM autoantibodies can affect this mechanism. By creating a proof-of-concept mouse model, we demonstrate a causal role for lysosomal lipids in blood-derived hepatic macrophages in mediating hepatic inflammation and initiation of fibrosis. Furthermore, our findings show that increasing anti-oxLDL IgM autoantibody levels reduces inflammation. Hence, therapies aimed at improving lipid-induced lysosomal dysfunction and blocking oxLDL-formation deserve further investigation in the context of NASH.
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