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

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

Author information

1
Division of Endocrinology, Metabolism & Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA.
2
Oncology Division, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
3
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.

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.

PMID:
25565205
PMCID:
PMC4287274
DOI:
10.1016/j.cmet.2014.12.002
[Indexed for MEDLINE]
Free PMC Article

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