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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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1-Deoxynojirimycin / analogs & derivatives*
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1-Deoxynojirimycin / pharmacology
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Acyltransferases / deficiency
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Acyltransferases / genetics
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Amidohydrolases / antagonists & inhibitors
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Animals
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CCAAT-Enhancer-Binding Proteins / genetics
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CCAAT-Enhancer-Binding Proteins / physiology*
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CHO Cells / drug effects
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CHO Cells / metabolism
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Ceramides / biosynthesis*
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Ceramides / pharmacology
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Cholesterol / metabolism
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Cricetinae
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Cricetulus
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Cycloserine / pharmacology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Enzyme Induction / drug effects
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Fatty Acids, Monounsaturated / pharmacology
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Fumonisins / pharmacology
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Genes, Reporter
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Hydroxymethylglutaryl-CoA Synthase / biosynthesis
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Hydroxymethylglutaryl-CoA Synthase / genetics
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Morpholines / pharmacology
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Myristates / pharmacology
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Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
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Propanolamines / pharmacology
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RNA Processing, Post-Transcriptional* / drug effects
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Serine C-Palmitoyltransferase
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Sphingolipids / pharmacology
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Sphingosine / analogs & derivatives*
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Sphingosine / pharmacology
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Sterol Regulatory Element Binding Protein 1
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Transcription Factors*
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Transcription, Genetic* / drug effects
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Transfection
Substances
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1-phenyl-2-palmitoylamino-3-morpholino-1-propanol
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2,3-N-octanoylsphingosine
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CCAAT-Enhancer-Binding Proteins
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Ceramides
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DNA-Binding Proteins
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Fatty Acids, Monounsaturated
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Fumonisins
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Morpholines
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Myristates
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N-hexanoyldihydrosphingosine
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Propanolamines
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Sphingolipids
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Sterol Regulatory Element Binding Protein 1
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Transcription Factors
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N-caproylsphingosine
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1-Deoxynojirimycin
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fumonisin B1
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2-(N-myristoylamino)-1-phenyl-1-propanol
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Cycloserine
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Cholesterol
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miglustat
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Acyltransferases
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Serine C-Palmitoyltransferase
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Hydroxymethylglutaryl-CoA Synthase
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Phosphotransferases (Alcohol Group Acceptor)
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sphingosine kinase
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Amidohydrolases
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N,N-dimethylsphingosine
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Sphingosine
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thermozymocidin