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Trapping of oxidized LDL in lysosomes of K upffer cells is a trigger for hepatic inflammation
Author(s) -
Bieghs Veerle,
Walenbergh Sofie M. A.,
Hendrikx Tim,
Gorp Patrick J.,
Verheyen Fons,
Olde Damink Steven W.,
Masclee Ad A.,
Koek Ger H.,
Hofker Marten H.,
Binder Christoph J.,
ShiriSverdlov Ronit
Publication year - 2013
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12170
Subject(s) - steatosis , inflammation , scavenger receptor , chemistry , lipid droplet , steatohepatitis , cytoplasm , pathogenesis , microbiology and biotechnology , fatty liver , ldl receptor , receptor , biochemistry , lipoprotein , medicine , endocrinology , biology , cholesterol , immunology , disease
Background & Aims Non‐alcoholic steatohepatitis ( NASH ) is characterized by steatosis and inflammation. The transition from steatosis towards NASH represents a key step in pathogenesis, as it will set the stage for further severe liver damage. Under normal conditions, lipoproteins that are endocytosed by K upffer cells ( KC s) are easily transferred from the lysosomes into the cytoplasm. Oxidized LDL (ox LDL ) that is taken up by the macrophages in vitro is trapped within the lysosomes, while acetylated LDL (ac LDL ) is leading to normal lysosomal hydrolysis, resulting in cytoplasmic storage. We have recently demonstrated that hepatic inflammation is correlated with lysosomal trapping of lipids. So far, a link between lysosomal trapping of ox LDL and inflammation was not established. We hypothesized that lysosomal trapping of ox LDL in KC s will lead to hepatic inflammation. Methods Ldlr −/− mice were injected with LDL , ac LDL and ox LDL and sacrificed after 2, 6 and 24 h. Results Electron microscopy of KC s demonstrated that after ox LDL injection, small lipid inclusions were present inside the lysosomes after all time points and were mostly pronounced after 6 and 24 h. In contrast, no lipid inclusions were present inside KC s after LDL or ac LDL injection. Hepatic expression of several inflammatory genes and scavenger receptors was higher after ox LDL injections compared with LDL or ac LDL . Conclusions These data suggest that trapping of ox LDL inside lysosomes of KC s in vivo is causally linked to increased hepatic inflammatory gene expression. Our novel observations provide new bases for prevention and treatment of NASH .