Blood-derived macrophages prone to accumulate lysosomal lipids trigger oxLDL-dependent murine hepatic inflammation

Tom Houben, Yvonne Oligschlaeger, Albert V. Bitorina, Tim Hendrikx, Sofie M. A. Walenbergh, Marie-Helene Lenders, Marion J. J. Gijbels, Fons Verheyen, Dieter Luetjohann, Marten H. Hofker, Christoph J. Binder, Ronit Shiri-Sverdlov*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

17 Citations (Web of Science)

Abstract

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.

Original languageEnglish
Article number12550
Number of pages9
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 2 Oct 2017

Keywords

  • LOW-DENSITY-LIPOPROTEIN
  • FATTY LIVER-DISEASE
  • OXIDATION-SPECIFIC EPITOPES
  • NONALCOHOLIC STEATOHEPATITIS
  • OXIDIZED LDL
  • CELL-DEATH
  • CHOLESTEROL CRYSTALS
  • MICE
  • ATHEROSCLEROSIS
  • EXPRESSION

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