title: Peroxisomal lipid synthesis regulates inflammation by sustaining neutrophil membrane phospholipid composition and viability.
abstract: Fatty acid synthase (FAS) is altered in metabolic disorders and cancer. Conventional FAS null mice die in utero, so effects of whole-body inhibition of lipogenesis following development are unknown. Inducible global knockout of FAS (iFASKO) in mice was lethal due to a disrupted intestinal barrier and leukopenia. Conditional loss of FAS was associated with the selective suppression of granulopoiesis without disrupting granulocytic differentiation. Transplantation of iFASKO bone marrow into wild-type mice followed by Cre induction resulted in selective neutrophil depletion, but not death. Impaired lipogenesis increased ER stress and apoptosis in neutrophils by preferentially decreasing peroxisome-derived membrane phospholipids containing ether bonds. Inducible global knockout of PexRAP, a peroxisomal enzyme required for ether lipid synthesis, also produced neutropenia. FAS knockdown in neutrophil-like HL-60 cells caused cell loss that was partially rescued by ether lipids. Inhibiting ether lipid synthesis selectively constrains neutrophil development, revealing an unrecognized pathway in immunometabolism.
authors.affiliation: Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Irfan J
authors.initials: IJ
authors.lastname: Lodhi
authors.affiliation: Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Xiaochao
authors.initials: X
authors.lastname: Wei
authors.affiliation: Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Yin
authors.affiliation: Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Chu
authors.initials: C
authors.lastname: Feng
authors.affiliation: Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Sangeeta
authors.initials: S
authors.lastname: Adak
authors.affiliation: Oncology Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Grazia
authors.initials: G
authors.lastname: Abou-Ezzi
authors.affiliation: Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Fong-Fu
authors.initials: FF
authors.lastname: Hsu
authors.affiliation: Oncology Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Link
authors.affiliation: Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: csemenko@wustl.edu.
authors.forename: Clay F
authors.initials: CF
authors.lastname: Semenkovich
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D016026:Bone Marrow Transplantation; D059865:Endoplasmic Reticulum Stress; D064429:Fatty Acid Synthases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D018922:HL-60 Cells; D006410:Hematopoiesis; D006801:Humans; D007249:Inflammation; D007413:Intestinal Mucosa / Q000378:metabolism; D008055:Lipids / Q000096:biosynthesis*; D050155:Lipogenesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D038042:Myelopoiesis; D009503:Neutropenia / Q000209:etiology / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism*; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism*; D013629:Tamoxifen / Q000633:toxicity
chemical_list: D008055:Lipids; D010743:Phospholipids; D013629:Tamoxifen; D064429:Fatty Acid Synthases