Session: OR05-Lipids: Regulation & Mechanism of Disease
Room 133 (Moscone Center)
Methods: We investigated the specific signals resulting in ACSL1 induction in macrophages to determine whether PPAR agonists or alternative stimuli regulate ACSL1 expression in this cell type. Next, we selectively examined signal transduction pathways involved in ACSL1 expression through use of pharmacological inhibitors, siRNA, and genetic knockout mice. Finally, we determined whether ACSL1 deficiency altered phospholipid composition in lipopolysaccharide (LPS)-stimulated macrophages.
Results: PPAR agonists do not stimulate ACSL1 expression in macrophages, whereas LPS, IFN-γ, TNFα, and Gram-negative pathogens significantly induce ACSL1 mRNA and protein. LPS-induced ACSL1 expression requires TLR4-TRIF-mediated signaling, but the effects of Escherichia coli (E. coli) on ACSL1 expression are TRIF-independent. IFN-γ induction of ACSL1 partially depends on JNK1/2 signaling, but JNK1/2 deficiency has no effect on LPS- or E. coli-mediated induction of ACSL1. ACSL1 expression is required for maximal LPS-induced turnover of phospholipid species.
Conclusion: The regulation and function of ACSL1 differ substantially in macrophages and insulin target tissues. Multiple pathways involved in inflammatory responses contribute to the induction of ACSL1 in macrophages, and the relative contribution of each implicated pathway depends on the specific inflammatory stimulus. ACSL1 in macrophages is required for LPS-stimulated turnover of several phospholipid species. These findings indicate a novel role for ACSL1 in innate immune function and, further, illustrate an interesting paradigm in which the same enzyme confers distinct biological effects in different cell types. Moreover, these disparate functions are paralleled by differences in the pathways that regulate its expression. Future studies are necessary to determine how ACSL1-dependent flux of phospholipid species contributes functionally to host defense and other facets of innate immune activity.
Nothing to Disclose: KBR, VZW, JN, DM, KB, BA, ML, KDS, MSH, AV, SP, CA, DAF, RJD, KEB
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