title: Palmitate and lipopolysaccharide trigger synergistic ceramide production in primary macrophages.
abstract: Macrophages play a key role in host defense and in tissue repair after injury. Emerging evidence suggests that macrophage dysfunction in states of lipid excess can contribute to the development of insulin resistance and may underlie inflammatory complications of diabetes. Ceramides are sphingolipids that modulate a variety of cellular responses including cell death, autophagy, insulin signaling, and inflammation. In this study we investigated the intersection between TLR4-mediated inflammatory signaling and saturated fatty acids with regard to ceramide generation. Primary macrophages treated with lipopolysaccharide (LPS) did not produce C16 ceramide, whereas palmitate exposure led to a modest increase in this sphingolipid. Strikingly, the combination of LPS and palmitate led to a synergistic increase in C16 ceramide. This response occurred via cross-talk at the level of de novo ceramide synthesis in the ER. The synergistic response required TLR4 signaling via MyD88 and TIR-domain-containing adaptor-inducing interferon beta (TRIF), whereas palmitate-induced ceramide production occurred independent of these inflammatory molecules. This ceramide response augmented IL-1β and TNFα release, a process that may contribute to the enhanced inflammatory response in metabolic diseases characterized by dyslipidemia.
authors.affiliation: Diabetic Cardiovascular Disease Center, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Schilling
authors.forename: Heather M
authors.initials: HM
authors.lastname: Machkovech
authors.forename: Li
authors.initials: L
authors.lastname: He
authors.forename: Rohini
authors.initials: R
authors.lastname: Sidhu
authors.forename: Hideji
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Kassandra
authors.initials: K
authors.lastname: Weber
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.forename: Jean E
authors.initials: JE
authors.lastname: Schaffer
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D000818:Animals; D053898:Biosynthetic Pathways / Q000187:drug effects; D002457:Cell Extracts; D002478:Cells, Cultured; D002518:Ceramides / Q000096:biosynthesis*; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010168:Palmitates / Q000494:pharmacology*; D013107:Sphingolipids / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D002457:Cell Extracts; D002518:Ceramides; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D010168:Palmitates; D013107:Sphingolipids; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C493487:Tlr4 protein, mouse