Acyl-CoA synthetase 1 is induced by Gram-negative bacteria and lipopolysaccharide and is required for phospholipid turnover in stimulated macrophages
Program in Molecular Medicine
Animals; Bone Marrow Cells; Coenzyme A Ligases; Female; Gram-Negative Bacteria; Immunity, Innate; Interferon-gamma; Lipopolysaccharides; MAP Kinase Kinase 4; Macrophages; Macrophages, Peritoneal; Male; Mice; Mice, Inbred C57BL; Models, Biological; Phospholipids; Signal Transduction
Biochemistry | Cell Biology | Cellular and Molecular Physiology | Molecular Biology
The enzyme acyl-CoA synthetase 1 (ACSL1) is induced by peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma in insulin target tissues, such as skeletal muscle and adipose tissue, and plays an important role in beta-oxidation in these tissues. In macrophages, however, ACSL1 mediates inflammatory effects without significant effects on beta-oxidation. Thus, the function of ACSL1 varies in different tissues. We therefore investigated the signals and signal transduction pathways resulting in ACSL1 induction in macrophages as well as the consequences of ACSL1 deficiency for phospholipid turnover in LPS-activated macrophages. LPS, Gram-negative bacteria, IFN-gamma, and TNFalpha all induce ACSL1 expression in macrophages, whereas PPAR agonists do not. LPS-induced ACSL1 expression is dependent on Toll-like receptor 4 (TLR4) and its adaptor protein TRIF (Toll-like receptor adaptor molecule 1) but does not require the MyD88 (myeloid differentiation primary response gene 88) arm of TLR4 signaling; nor does it require STAT1 (signal transducer and activator of transcription 1) for maximal induction. Furthermore, ACSL1 deletion attenuates phospholipid turnover in LPS-stimulated macrophages. Thus, the regulation and biological function of ACSL1 in macrophages differ markedly from that in insulin target tissues. These results suggest that ACSL1 may have an important role in the innate immune response. Further, these findings illustrate an interesting paradigm in which the same enzyme, ACSL1, confers distinct biological effects in different cell types, and these disparate functions are paralleled by differences in the pathways that regulate its expression.
DOI of Published Version
J Biol Chem. 2013 Apr 5;288(14):9957-70. doi: 10.1074/jbc.M113.458372. Epub 2013 Feb 20. Link to article on publisher's site
The Journal of biological chemistry
Rubinow, Katya B.; Wall, Valerie Z.; Nelson, Joel; Mar, Daniel; Bomsztyk, Karol; Askari, Bardia; Lai, Marvin A.; Smith, Kelly D.; Han, Myoung Souk; Vivekanandan-Giri, Anuradha; Pennathur, Subramaniam; Albert, Carolyn J.; Ford, David A.; Davis, Roger J.; and Bornfeldt, Karin E., "Acyl-CoA synthetase 1 is induced by Gram-negative bacteria and lipopolysaccharide and is required for phospholipid turnover in stimulated macrophages" (2013). Davis Lab Publications. 46.