Peroxisomal lipid synthesis regulates inflammation by sustaining neutrophil membrane phospholipid composition and viability

Cell Metab. 2015 Jan 6;21(1):51-64. doi: 10.1016/j.cmet.2014.12.002.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • Bone Marrow Transplantation
  • Endoplasmic Reticulum Stress
  • Fatty Acid Synthases / deficiency
  • Fatty Acid Synthases / genetics
  • Fatty Acid Synthases / metabolism*
  • Gene Expression / drug effects
  • HL-60 Cells
  • Hematopoiesis
  • Humans
  • Inflammation
  • Intestinal Mucosa / metabolism
  • Lipids / biosynthesis*
  • Lipogenesis
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myelopoiesis
  • Neutropenia / etiology
  • Neutropenia / metabolism
  • Neutrophils / metabolism*
  • Phospholipids / chemistry
  • Phospholipids / metabolism*
  • Tamoxifen / toxicity

Substances

  • Lipids
  • Phospholipids
  • Tamoxifen
  • Fatty Acid Synthases