title: Saturated fatty acid palmitate induces extracellular release of histone H3: a possible mechanistic basis for high-fat diet-induced inflammation and thrombosis.
abstract: Chronic low-grade inflammation is a key contributor to high-fat diet (HFD)-related diseases, such as type 2 diabetes, non-alcoholic steatohepatitis, and atherosclerosis. The inflammation is characterized by infiltration of inflammatory cells, particularly macrophages, into obese adipose tissue. However, the molecular mechanisms by which a HFD induces low-grade inflammation are poorly understood. Here, we show that histone H3, a major protein component of chromatin, is released into the extracellular space when mice are fed a HFD or macrophages are stimulated with the saturated fatty acid palmitate. In a murine macrophage cell line, RAW 264.7, palmitate activated reactive oxygen species (ROS) production and JNK signaling. Inhibitors of these pathways dampened palmitate-induced histone H3 release, suggesting that the extracellular release of histone H3 was mediated, in part, through ROS and JNK signaling. Extracellular histone activated endothelial cells to express the adhesion molecules ICAM-1 and VCAM-1 and the procoagulant molecule tissue factor, which are known to contribute to inflammatory cell recruitment and thrombosis. These results suggest the possible contribution of extracellular histone to the pathogenesis of HFD-induced inflammation and thrombosis.
authors.affiliation: Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Chandan
authors.initials: C
authors.lastname: Shrestha
authors.forename: Takashi
authors.initials: T
authors.lastname: Ito
authors.forename: Ko-ichi
authors.initials: K
authors.lastname: Kawahara
authors.forename: Binita
authors.initials: B
authors.lastname: Shrestha
authors.forename: Munekazu
authors.initials: M
authors.lastname: Yamakuchi
authors.forename: Teruto
authors.initials: T
authors.lastname: Hashiguchi
authors.forename: Ikuro
authors.initials: I
authors.lastname: Maruyama
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D002448:Cell Adhesion; D002460:Cell Line; D002470:Cell Survival; D003029:Coagulants / Q000378:metabolism; D059305:Diet, High-Fat; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019308:Palmitic Acid / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D003029:Coagulants; D006657:Histones; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D019308:Palmitic Acid; D048670:MAP Kinase Kinase 4
keywords: High-fat diet; Histone H3; Inflammation; JNK; Palmitate; ROS