Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids
Long-chain acyl-CoA synthetase 1 (ACSL1) catalyzes the conversion of long-chain fatty acids to acyl-CoAs. ACSL1 is required for β-oxidation in tissues that rely on fatty acids as fuel, but no consensus exists on why ACSL1 is induced by inflammatory mediators in immune cells. We used a comprehensive...
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Elsevier
2025-01-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227524002359 |
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| author | Shelley Barnhart Masami Shimizu-Albergine Eyal Kedar Vishal Kothari Baohai Shao Melissa Krueger Cheng-Chieh Hsu Jingjing Tang Jenny E. Kanter Farah Kramer Danijel Djukovic Vadim Pascua Yueh-Ming Loo Lucrezia Colonna Sadie J. Van den Bogaerde Jie An Michael Gale, Jr. Karen Reue Edward A. Fisher Sina A. Gharib Keith B. Elkon Karin E. Bornfeldt |
| author_facet | Shelley Barnhart Masami Shimizu-Albergine Eyal Kedar Vishal Kothari Baohai Shao Melissa Krueger Cheng-Chieh Hsu Jingjing Tang Jenny E. Kanter Farah Kramer Danijel Djukovic Vadim Pascua Yueh-Ming Loo Lucrezia Colonna Sadie J. Van den Bogaerde Jie An Michael Gale, Jr. Karen Reue Edward A. Fisher Sina A. Gharib Keith B. Elkon Karin E. Bornfeldt |
| author_sort | Shelley Barnhart |
| collection | DOAJ |
| description | Long-chain acyl-CoA synthetase 1 (ACSL1) catalyzes the conversion of long-chain fatty acids to acyl-CoAs. ACSL1 is required for β-oxidation in tissues that rely on fatty acids as fuel, but no consensus exists on why ACSL1 is induced by inflammatory mediators in immune cells. We used a comprehensive and unbiased approach to investigate the role of ACSL1 induction by interferon type I (IFN-I) in myeloid cells in vitro and in a mouse model of IFN-I overproduction. Our results show that IFN-I induces ACSL1 in macrophages via its interferon-α/β receptor, and consequently that expression of ACSL1 is increased in myeloid cells from individuals with systemic lupus erythematosus (SLE), an autoimmune condition characterized by increased IFN production. Taking advantage of a myeloid cell-targeted ACSL1-deficient mouse model and a series of lipidomics, proteomics, metabolomics and functional analyses, we show that IFN-I leverages induction of ACSL1 to increase accumulation of fully saturated phosphatidic acid species in macrophages. Conversely, ACSL1 induction is not needed for IFN-I’s ability to induce the prototypical IFN-stimulated protein signature or to suppress proliferation or macrophage metabolism. Loss of ACSL1 in IFN-I stimulated myeloid cells enhances apoptosis and secondary necrosis in vitro, especially in the presence of increased saturated fatty acid load, and in a mouse model of atherosclerosis associated with IFN overproduction, resulting in larger lesion necrotic cores. We propose that ACSL1 induction is a mechanism used by IFN-I to increase phosphatidic acid saturation while protecting the cells from saturated fatty acid-induced cell death. |
| format | Article |
| id | doaj-art-4dd403f1c0694d14b906ece1a2ae113a |
| institution | Kabale University |
| issn | 0022-2275 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-4dd403f1c0694d14b906ece1a2ae113a2025-01-30T05:12:41ZengElsevierJournal of Lipid Research0022-22752025-01-01661100730Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acidsShelley Barnhart0Masami Shimizu-Albergine1Eyal Kedar2Vishal Kothari3Baohai Shao4Melissa Krueger5Cheng-Chieh Hsu6Jingjing Tang7Jenny E. Kanter8Farah Kramer9Danijel Djukovic10Vadim Pascua11Yueh-Ming Loo12Lucrezia Colonna13Sadie J. Van den Bogaerde14Jie An15Michael Gale, Jr.16Karen Reue17Edward A. Fisher18Sina A. Gharib19Keith B. Elkon20Karin E. Bornfeldt21Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA; UW Medicine Diabetes Institute, University of Washington, Seattle, WADivision of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA; UW Medicine Diabetes Institute, University of Washington, Seattle, WADivision of Rheumatology, University of Washington, Seattle, WADivision of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA; UW Medicine Diabetes Institute, University of Washington, Seattle, WADivision of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA; UW Medicine Diabetes Institute, University of Washington, Seattle, WADivision of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WADivision of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA; UW Medicine Diabetes Institute, University of Washington, Seattle, WADivision of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA; UW Medicine Diabetes Institute, University of Washington, Seattle, WADivision of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA; UW Medicine Diabetes Institute, University of Washington, Seattle, WADivision of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA; UW Medicine Diabetes Institute, University of Washington, Seattle, WADepartment of Anesthesiology and Pain Medicine, Northwest Metabolomics Research Center, University of Washington, Seattle, WADepartment of Anesthesiology and Pain Medicine, Northwest Metabolomics Research Center, University of Washington, Seattle, WADepartment of Immunology, University of Washington, Seattle, WADivision of Rheumatology, University of Washington, Seattle, WADivision of Rheumatology, University of Washington, Seattle, WADivision of Rheumatology, University of Washington, Seattle, WADepartment of Immunology, University of Washington, Seattle, WADepartment of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CADivision of Cardiology, Department of Medicine, New York University Grossman School of Medicine, New York, NYDivision of Pulmonary, Critical Care and Sleep Medicine, University of Washington, Seattle, WADivision of Rheumatology, University of Washington, Seattle, WADivision of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington, Seattle, WA; UW Medicine Diabetes Institute, University of Washington, Seattle, WA; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA; For correspondence: Karin E. BornfeldtLong-chain acyl-CoA synthetase 1 (ACSL1) catalyzes the conversion of long-chain fatty acids to acyl-CoAs. ACSL1 is required for β-oxidation in tissues that rely on fatty acids as fuel, but no consensus exists on why ACSL1 is induced by inflammatory mediators in immune cells. We used a comprehensive and unbiased approach to investigate the role of ACSL1 induction by interferon type I (IFN-I) in myeloid cells in vitro and in a mouse model of IFN-I overproduction. Our results show that IFN-I induces ACSL1 in macrophages via its interferon-α/β receptor, and consequently that expression of ACSL1 is increased in myeloid cells from individuals with systemic lupus erythematosus (SLE), an autoimmune condition characterized by increased IFN production. Taking advantage of a myeloid cell-targeted ACSL1-deficient mouse model and a series of lipidomics, proteomics, metabolomics and functional analyses, we show that IFN-I leverages induction of ACSL1 to increase accumulation of fully saturated phosphatidic acid species in macrophages. Conversely, ACSL1 induction is not needed for IFN-I’s ability to induce the prototypical IFN-stimulated protein signature or to suppress proliferation or macrophage metabolism. Loss of ACSL1 in IFN-I stimulated myeloid cells enhances apoptosis and secondary necrosis in vitro, especially in the presence of increased saturated fatty acid load, and in a mouse model of atherosclerosis associated with IFN overproduction, resulting in larger lesion necrotic cores. We propose that ACSL1 induction is a mechanism used by IFN-I to increase phosphatidic acid saturation while protecting the cells from saturated fatty acid-induced cell death.http://www.sciencedirect.com/science/article/pii/S0022227524002359Bis[monoacylglycerol]phosphatesenzymology/Enzyme mechanismsglycerophospholipidsinflammationlipotoxicitymacrophage |
| spellingShingle | Shelley Barnhart Masami Shimizu-Albergine Eyal Kedar Vishal Kothari Baohai Shao Melissa Krueger Cheng-Chieh Hsu Jingjing Tang Jenny E. Kanter Farah Kramer Danijel Djukovic Vadim Pascua Yueh-Ming Loo Lucrezia Colonna Sadie J. Van den Bogaerde Jie An Michael Gale, Jr. Karen Reue Edward A. Fisher Sina A. Gharib Keith B. Elkon Karin E. Bornfeldt Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids Journal of Lipid Research Bis[monoacylglycerol]phosphates enzymology/Enzyme mechanisms glycerophospholipids inflammation lipotoxicity macrophage |
| title | Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids |
| title_full | Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids |
| title_fullStr | Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids |
| title_full_unstemmed | Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids |
| title_short | Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids |
| title_sort | type i ifn induces long chain acyl coa synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids |
| topic | Bis[monoacylglycerol]phosphates enzymology/Enzyme mechanisms glycerophospholipids inflammation lipotoxicity macrophage |
| url | http://www.sciencedirect.com/science/article/pii/S0022227524002359 |
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