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ORMDL proteins regulate ceramide levels during sterile inflammation.

Lin Cai1, Clement Oyeniran2, Debolina D Biswas2

  • 1School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China Department of Biochemistry and Molecular Biology and the Massey Cancer Center, Virginia Commonwealth University School of Medicine, Richmond, VA 23298.

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Summary
This summary is machine-generated.

Mammalian ORMDL proteins regulate ceramide levels, a key molecule in inflammation. Downregulation of ORMDL proteins increases ceramide precursors, suggesting their role in IL-1-mediated sterile inflammation.

Keywords:
ORM-like proteinceramide synthaseserine palmitoyltransferasesphingolipids

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Immunology

Background:

  • Ceramide, a bioactive sphingolipid, is crucial for inflammation and implicated in IL-1-mediated events.
  • While ceramide generation via sphingomyelinases is understood, the de novo pathway's role remains unclear.
  • Yeast ORM1/ORM2 proteins inhibit serine palmitoyltransferase, regulating de novo ceramide biosynthesis.

Purpose of the Study:

  • To investigate the function of mammalian ORM-like (ORMDL) proteins in regulating ceramide levels.
  • To determine the role of ORMDLs in de novo ceramide biosynthesis.
  • To explore ORMDL involvement in IL-1-mediated sterile inflammation.

Main Methods:

  • Utilized HepG2 liver cells and [U-(13)C]palmitate incorporation to trace de novo biosynthesis.
  • Examined the impact of ORMDL downregulation on ceramide precursors.
  • Investigated ORMDL protein and ceramide levels in response to IL-1, oncostatin M, and in a mouse model of sterile inflammation.

Main Results:

  • Downregulation of ORMDL3 in HepG2 cells increased de novo synthesis of dihydrosphingosine and dihydroceramide.
  • IL-1 and oncostatin M elevated dihydroceramide and ceramide levels while decreasing ORMDL proteins.
  • In mice, sterile inflammation led to ORMDL downregulation in the liver, increased liver ceramide, and blood ceramide accumulation.

Conclusions:

  • Mammalian ORMDLs (ORMDL1-3) are involved in regulating de novo ceramide biosynthesis.
  • ORMDL protein levels decrease in response to inflammatory stimuli (IL-1, oncostatin M).
  • ORMDLs are implicated in the regulation of ceramide metabolism during IL-1-mediated sterile inflammation.