Inhibition of serine palmitoyltransferase delays the onset of radiation-induced pulmonary fibrosis through the negative regulation of sphingosine kinase-1 expression

J Lipid Res. 2012 Aug;53(8):1553-68. doi: 10.1194/jlr.M026039. Epub 2012 May 21.


The enforcement of sphingosine-1-phosphate (S1P) signaling network protects from radiation-induced pneumonitis. We now demonstrate that, in contrast to early postirradiation period, late postirradiation sphingosine kinase-1 (SphK1) and sphingoid base-1-phosphates are associated with radiation-induced pulmonary fibrosis (RIF). Using the mouse model, we demonstrate that RIF is characterized by a marked upregulation of S1P and dihydrosphingosine-1-phosphate (DHS1P) levels in the lung tissue and in circulation accompanied by increased lung SphK1 expression and activity. Inhibition of sphingolipid de novo biosynthesis by targeting serine palmitoyltransferase (SPT) with myriocin reduced radiation-induced pulmonary inflammation and delayed the onset of RIF as evidenced by increased animal lifespan and decreased expression of markers of fibrogenesis, such as collagen and α-smooth muscle actin (α-SMA), in the lung. Long-term inhibition of SPT also decreased radiation-induced SphK activity in the lung and the levels of S1P-DHS1P in the lung tissue and in circulation. In vitro, inhibition or silencing of serine palmitoyltransferase attenuated transforming growth factor-β1 (TGF-β)-induced upregulation of α-SMA through the negative regulation of SphK1 expression in normal human lung fibroblasts. These data demonstrate a novel role for SPT in regulating TGF-β signaling and fibrogenesis that is linked to the regulation of SphK1 expression and S1P-DHS1P formation.

Publication types

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

MeSH terms

  • Animals
  • Enzyme Inhibitors / pharmacology*
  • Fatty Acids, Monounsaturated / pharmacology*
  • Female
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Gene Expression Regulation, Enzymologic / radiation effects
  • Humans
  • Mice
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Pulmonary Fibrosis / enzymology
  • Pulmonary Fibrosis / genetics
  • Pulmonary Fibrosis / pathology
  • Pulmonary Fibrosis / prevention & control*
  • Radiation Injuries, Experimental / enzymology
  • Radiation Injuries, Experimental / genetics
  • Radiation Injuries, Experimental / pathology
  • Radiation Injuries, Experimental / prevention & control*
  • Serine C-Palmitoyltransferase / antagonists & inhibitors*
  • Signal Transduction / drug effects
  • Signal Transduction / radiation effects
  • Sphingosine / analogs & derivatives
  • Sphingosine / metabolism
  • Thorax / radiation effects
  • Time Factors
  • Transforming Growth Factor beta / metabolism
  • Up-Regulation / drug effects
  • Up-Regulation / radiation effects


  • Enzyme Inhibitors
  • Fatty Acids, Monounsaturated
  • Transforming Growth Factor beta
  • dihydrosphingosine 1-phosphate
  • Serine C-Palmitoyltransferase
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Sphingosine
  • thermozymocidin