OR05-4 Acyl-CoA Synthetase 1 is Induced by Gram-Negative Bacteria and Lipopolysaccharide and is Required for Phospholipid Turnover in Stimulated Macrophages

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR05-Lipids: Regulation & Mechanism of Disease
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 12:15 PM
Room 133 (Moscone Center)
Katya Bronwyn Rubinow*1, Valerie Z Wall2, Joel Nelson2, Daniel Mar2, Karol Bomsztyk2, Bardia Askari2, Marvin Lai2, Kelly D Smith2, Myoung Sook Han3, Anuradha Vivekanandan-Giri4, Subramaniam Pennathur4, Carolyn Albert5, David A Ford5, Roger J Davis6 and Karin E Bornfeldt2
1University of Washington, Seattle, WA, 2University of Washington, 3HHMI/UMASS Med Schl, 4University of Michigan, 5Saint Louis University School of Medicine, 6HHMI/UMASS Med Schl, Worcester, MA
Background:Acyl-CoA synthetase 1 (ACSL1) mediates inflammatory effects in macrophages, and myeloid cell-targeted ACSL1 deficiency protects mice from early atheroma formation in models of type 1 diabetes.  In insulin target tissues, ACSL1 plays a predominant role in fatty acid β-oxidation, and its transcription is mediated by peroxisome proliferator-activated receptor (PPAR) α and γ.  However, its regulation and biological role in macrophages remain largely unknown.

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

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH grants HL062887, HL092969, HL097365 (KEB); 6K12HD053984 (KBR); AI062859 (KDS); HL074214, HL111906 (DAF); DK083310, R37 DK45978 and JDRF grant 42-2009-779 (KB); Diabetes Research Center at the University of Washington, DK017047 (KEB); NIH training grant T32DK007247 (KBR); NIH training grant T32HL007312 (JN)