Ceramide synthesis correlates with the posttranscriptional regulation of the sterol-regulatory element-binding protein

Arterioscler Thromb Vasc Biol. 2004 May;24(5):943-8. doi: 10.1161/01.atv.0000125703.20434.4d.

Abstract

Objective: Sterol-regulatory element-binding proteins (SREBPs) regulate transcription of genes of lipid metabolism. Ceramide decreases transcriptionally active SREBP levels independently of intracellular cholesterol levels. Mechanisms of the ceramide-mediated decrease of SREBP levels were investigated.

Methods and results: Experiments were performed in Chinese hamster ovary cells. Inhibition of ceramide synthesis with myriocin, cycloserine, or fumonisin decreases levels of transcriptionally active SREBP and reduces SRE-mediated gene transcription. When ceramide synthesis is increased through exogenous sphingosine or inhibition of sphingosine kinase, SRE-mediated gene transcription is increased. The important role of ceramide synthesis in SRE-mediated gene transcription is confirmed in LY-B cells that do not synthesize ceramide de novo. LY-B cells fail to increase SRE-mediated gene transcription in sterol depletion.

Conclusions: Ceramide synthesis correlates with the generation of transcriptionally active SREBP and SRE-mediated gene transcription. Inhibition of ceramide synthesis decreases levels of transcriptionally active SREBP and SRE-mediated gene transcription. It is hypothesized that the process of ongoing ceramide synthesis contributes to the physiological processing of SREBP, perhaps affecting ER-to-Golgi trafficking. Taken together, modification of ceramide synthesis could be a novel target for drug development in the pharmacologic modification of SRE-dependent pathways.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 1-Deoxynojirimycin / analogs & derivatives*
  • 1-Deoxynojirimycin / pharmacology
  • Acyltransferases / deficiency
  • Acyltransferases / genetics
  • Amidohydrolases / antagonists & inhibitors
  • Animals
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / physiology*
  • CHO Cells / drug effects
  • CHO Cells / metabolism
  • Ceramides / biosynthesis*
  • Ceramides / pharmacology
  • Cholesterol / metabolism
  • Cricetinae
  • Cricetulus
  • Cycloserine / pharmacology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Enzyme Induction / drug effects
  • Fatty Acids, Monounsaturated / pharmacology
  • Fumonisins / pharmacology
  • Genes, Reporter
  • Hydroxymethylglutaryl-CoA Synthase / biosynthesis
  • Hydroxymethylglutaryl-CoA Synthase / genetics
  • Morpholines / pharmacology
  • Myristates / pharmacology
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Propanolamines / pharmacology
  • RNA Processing, Post-Transcriptional* / drug effects
  • Serine C-Palmitoyltransferase
  • Sphingolipids / pharmacology
  • Sphingosine / analogs & derivatives*
  • Sphingosine / pharmacology
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors*
  • Transcription, Genetic* / drug effects
  • Transfection

Substances

  • 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol
  • 2,3-N-octanoylsphingosine
  • CCAAT-Enhancer-Binding Proteins
  • Ceramides
  • DNA-Binding Proteins
  • Fatty Acids, Monounsaturated
  • Fumonisins
  • Morpholines
  • Myristates
  • N-hexanoyldihydrosphingosine
  • Propanolamines
  • Sphingolipids
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors
  • N-caproylsphingosine
  • 1-Deoxynojirimycin
  • fumonisin B1
  • 2-(N-myristoylamino)-1-phenyl-1-propanol
  • Cycloserine
  • Cholesterol
  • miglustat
  • Acyltransferases
  • Serine C-Palmitoyltransferase
  • Hydroxymethylglutaryl-CoA Synthase
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Amidohydrolases
  • N,N-dimethylsphingosine
  • Sphingosine
  • thermozymocidin