TY - JOUR
T1 - Blood-derived macrophages prone to accumulate lysosomal lipids trigger oxLDL-dependent murine hepatic inflammation
AU - Houben, Tom
AU - Oligschlaeger, Yvonne
AU - Bitorina, Albert V.
AU - Hendrikx, Tim
AU - Walenbergh, Sofie M. A.
AU - Lenders, Marie-Helene
AU - Gijbels, Marion J. J.
AU - Verheyen, Fons
AU - Luetjohann, Dieter
AU - Hofker, Marten H.
AU - Binder, Christoph J.
AU - Shiri-Sverdlov, Ronit
PY - 2017/10/2
Y1 - 2017/10/2
N2 - 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.
AB - 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.
KW - LOW-DENSITY-LIPOPROTEIN
KW - FATTY LIVER-DISEASE
KW - OXIDATION-SPECIFIC EPITOPES
KW - NONALCOHOLIC STEATOHEPATITIS
KW - OXIDIZED LDL
KW - CELL-DEATH
KW - CHOLESTEROL CRYSTALS
KW - MICE
KW - ATHEROSCLEROSIS
KW - EXPRESSION
U2 - 10.1038/s41598-017-13058-z
DO - 10.1038/s41598-017-13058-z
M3 - Article
C2 - 28970532
SN - 2045-2322
VL - 7
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 12550
ER -