title: Acyl-CoA synthetase 1 is induced by Gram-negative bacteria and lipopolysaccharide and is required for phospholipid turnover in stimulated macrophages.
abstract: The enzyme acyl-CoA synthetase 1 (ACSL1) is induced by peroxisome proliferator-activated receptor α (PPARα) and PPARγ in insulin target tissues, such as skeletal muscle and adipose tissue, and plays an important role in β-oxidation in these tissues. In macrophages, however, ACSL1 mediates inflammatory effects without significant effects on β-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-γ, and TNFα 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.
authors: Diabetes and Obesity Center of Excellence, Departments of Medicine, University of Washington, Seattle, Washington 98109.
authors: Katya B
authors: KB
authors: Rubinow
authors: Diabetes and Obesity Center of Excellence, Departments of Medicine, University of Washington, Seattle, Washington 98109.
authors: Valerie Z
authors: VZ
authors: Wall
authors: Diabetes and Obesity Center of Excellence, Departments of Medicine, University of Washington, Seattle, Washington 98109.
authors: Joel
authors: J
authors: Nelson
authors: Diabetes and Obesity Center of Excellence, Departments of Medicine, University of Washington, Seattle, Washington 98109.
authors: Daniel
authors: D
authors: Mar
authors: Diabetes and Obesity Center of Excellence, Departments of Medicine, University of Washington, Seattle, Washington 98109.
authors: Karol
authors: K
authors: Bomsztyk
authors: Diabetes and Obesity Center of Excellence, Departments of Pathology, University of Washington, Seattle, Washington 98109.
authors: Bardia
authors: B
authors: Askari
authors: Diabetes and Obesity Center of Excellence, Departments of Pathology, University of Washington, Seattle, Washington 98109.
authors: Marvin A
authors: MA
authors: Lai
authors: Diabetes and Obesity Center of Excellence, Departments of Pathology, University of Washington, Seattle, Washington 98109.
authors: Kelly D
authors: KD
authors: Smith
authors: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors: Myoung Sook
authors: MS
authors: Han
authors: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109.
authors: Anuradha
authors: A
authors: Vivekanandan-Giri
authors: Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109.
authors: Subramaniam
authors: S
authors: Pennathur
authors: Department of Biochemistry and Molecular Biology and Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, Missouri 63104.
authors: Carolyn J
authors: CJ
authors: Albert
authors: Department of Biochemistry and Molecular Biology and Center for Cardiovascular Research, Saint Louis University School of Medicine, St. Louis, Missouri 63104.
authors: David A
authors: DA
authors: Ford
authors: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605.
authors: Roger J
authors: RJ
authors: Davis
authors: Diabetes and Obesity Center of Excellence, Departments of Medicine, University of Washington, Seattle, Washington 98109; Diabetes and Obesity Center of Excellence, Departments of Pathology, University of Washington, Seattle, Washington 98109. Electronic address: bornf@uw.edu.
authors: Karin E
authors: KE
authors: Bornfeldt
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D003066:Coenzyme A Ligases / Q000378:metabolism*; D005260:Female; D006090:Gram-Negative Bacteria / Q000378:metabolism*; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010743:Phospholipids / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008070:Lipopolysaccharides; D010743:Phospholipids; D007371:Interferon-gamma; D048670:MAP Kinase Kinase 4; C544400:ACSL1 protein, mouse; D003066:Coenzyme A Ligases