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


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.
Worgall
Tilla S
TS
Department of Pathology, Columbia University, New York, NY 10032, USA. tpw7@columbia.edu
Juliano
Rebecca A
RA
Seo
Toru
T
Deckelbaum
Richard J
RJ
D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000217:Acyltransferases / Q000172:deficiency / Q000235:genetics; D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000502:physiology*; D016466:CHO Cells / Q000187:drug effects / Q000378:metabolism; D002518:Ceramides / Q000096:biosynthesis* / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003523:Cycloserine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004790:Enzyme Induction / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D037341:Fumonisins / Q000494:pharmacology; D017930:Genes, Reporter; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000096:biosynthesis / Q000235:genetics; D009025:Morpholines / Q000494:pharmacology; D009226:Myristates / Q000494:pharmacology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors; D011412:Propanolamines / Q000494:pharmacology; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects; D051102:Serine C-Palmitoyltransferase; D013107:Sphingolipids / Q000494:pharmacology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014162:Transfection; D000099157:Sphingosine Kinase
D017485:1-Deoxynojirimycin; D000217:Acyltransferases; D000581:Amidohydrolases; D022762:CCAAT-Enhancer-Binding Proteins; D002518:Ceramides; D002784:Cholesterol; D003523:Cycloserine; D004268:DNA-Binding Proteins; D005229:Fatty Acids, Monounsaturated; D037341:Fumonisins; D006904:Hydroxymethylglutaryl-CoA Synthase; D009025:Morpholines; D009226:Myristates; D017853:Phosphotransferases (Alcohol Group Acceptor); D011412:Propanolamines; D051102:Serine C-Palmitoyltransferase; D013107:Sphingolipids; D013110:Sphingosine; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D000099157:Sphingosine Kinase; C095823:1-phenyl-2-palmitoylamino-3-morpholino-1-propanol; C066099:2,3-N-octanoylsphingosine; C492068:N-hexanoyldihydrosphingosine; C101954:N-caproylsphingosine; C056933:fumonisin B1; C099657:2-(N-myristoylamino)-1-phenyl-1-propanol; C059896:miglustat; C061800:N,N-dimethylsphingosine; C001996:thermozymocidin