Palmitate and lipopolysaccharide trigger synergistic ceramide production in primary macrophages

Joel D. Schilling, Heather M. Machkovech, Li He, Rohini Sidhu, Hideji Fujiwara, Kassandra Weber, Daniel S. Ory, Jean E. Schaffer

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

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.

Original languageEnglish
Pages (from-to)2923-2932
Number of pages10
JournalJournal of Biological Chemistry
Volume288
Issue number5
DOIs
StatePublished - Feb 1 2013

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