Development and Application of FASA, a Model for Quantifying Fatty Acid Metabolism Using Stable Isotope Labeling
Joseph P. Argus,
Moses Q. Wilks,
Quan D. Zhou,
Wei Yuan Hsieh,
Elvira Khialeeva,
Xen Ping Hoi,
Viet Bui,
Shili Xu,
Amy K. Yu,
Eric S. Wang,
Harvey R. Herschman,
Kevin J. Williams,
Steven J. Bensinger
Affiliations
Joseph P. Argus
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, 615 Charles E. Young Drive East, Los Angeles, CA 90095, USA
Moses Q. Wilks
Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, 149, 13th Street, Charlestown, MA 02129, USA
Quan D. Zhou
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, 615 Charles E. Young Drive East, Los Angeles, CA 90095, USA; Department of Surgical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
Wei Yuan Hsieh
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, 615 Charles E. Young Drive East, Los Angeles, CA 90095, USA
Elvira Khialeeva
Molecular Biology Institute, University of California, Los Angeles, 611 Charles E. Young Drive East, Los Angeles, CA 90095, USA
Xen Ping Hoi
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, 615 Charles E. Young Drive East, Los Angeles, CA 90095, USA
Viet Bui
Division of Rheumatology, David Geffen School of Medicine, University of California, Los Angeles, 1000 Veteran Avenue, Los Angeles, CA 90095, USA
Shili Xu
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, 615 Charles E. Young Drive East, Los Angeles, CA 90095, USA
Amy K. Yu
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, 615 Charles E. Young Drive East, Los Angeles, CA 90095, USA
Eric S. Wang
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, 615 Charles E. Young Drive East, Los Angeles, CA 90095, USA
Harvey R. Herschman
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, 615 Charles E. Young Drive East, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, 611 Charles E. Young Drive East, Los Angeles, CA 90095, USA
Kevin J. Williams
Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, 615 Charles E. Young Drive East, Los Angeles, CA 90095, USA
Steven J. Bensinger
Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, 615 Charles E. Young Drive East, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine, University of California, Los Angeles, 615 Charles E. Young Drive East, Los Angeles, CA 90095, USA; Corresponding author
Summary: It is well understood that fatty acids can be synthesized, imported, and modified to meet requisite demands in cells. However, following the movement of fatty acids through the multiplicity of these metabolic steps has remained difficult. To better address this problem, we developed Fatty Acid Source Analysis (FASA), a model that defines the contribution of synthesis, import, and elongation pathways to fatty acid homeostasis in saturated, monounsaturated, and polyunsaturated fatty acid pools. Application of FASA demonstrated that elongation can be a major contributor to cellular fatty acid content and showed that distinct pro-inflammatory stimuli (e.g., Toll-like receptors 2, 3, or 4) specifically reprogram homeostasis of fatty acids by differential utilization of synthetic and elongation pathways in macrophages. In sum, this modeling approach significantly advances our ability to interrogate cellular fatty acid metabolism and provides insight into how cells dynamically reshape their lipidomes in response to metabolic or inflammatory signals. : Argus et al. developed Fatty Acid Source Analysis (FASA), a model that quantifies cellular fatty acid synthesis, elongation, and import. FASA is used to demonstrate that elongation can be a major contributor to cellular fatty acid content and that different stimuli reprogram macrophage fatty acid elongation pathways in distinct ways. Keywords: fatty acid homeostasis, fatty acid modeling, stable isotope labeling
