We have previously demonstrated that chronic exposure of 3T3-L1 adipocytes to tumour necrosis factor-α (TNF) resulted in a marked decrease (∼ 90%) in cellular GLUT4 (insulin-responsive glucose transporter) mRNA content as a result of a decreased transcription rate of the GLUT4 gene (∼ 75%) and a reduced half-life of its mRNA (9 to 4.5 h). Investigation of the signalling mechanism responsible for this regulation demonstrated that in the 3T3-L1 adipocytes, sphingomyelin levels decreased to 50% of control levels within 40 min of exposure to TNF, consistent with activation of a sphingomyelinase. In the same manner as with TNF, treatment of the adipocytes with 1-3 µM C6-ceramide, a membrane-permeable analogue of ceramide, decreased GLUT4 mRNA content by ∼ 60%. Subsequent investigations revealed that transcription of the GLUT4 gene was reduced by ∼ 65% in response to C6-ceramide, demonstrating that the decrease in mRNA content is mediated by a reduction in the transcription of the gene. No effect on GLUT4 mRNA stability was observed after exposure of the adipocytes to C6-ceramide. These observations are interesting in light of our previous data demonstrating that TNF affects both GLUT4 transcription and mRNA stability in the 3T3-L1 adipocytes. In conclusion, the effect of ceramide on GLUT4 gene expression is at the level of transcription, suggesting that another pathway controls mRNA stability. These data establish that ceramide-initiated signal transduction pathways exist within the adipocyte, and provide a potential mechanism for control of GLUT4 gene expression.
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October 1996
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Research Article|
October 01 1996
Lipid mediators of insulin resistance: ceramide signalling down-regulates GLUT4 gene transcription in 3T3-L1 adipocytes
Sheree D LONG;
Sheree D LONG
1Department of Biochemistry, School of Medicine, East Carolina University, Greenville, NC 27858, U.S.A.
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Phillip H PEKALA
Phillip H PEKALA
*
1Department of Biochemistry, School of Medicine, East Carolina University, Greenville, NC 27858, U.S.A.
*To whom correspondence should be addressed.
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Biochem J (1996) 319 (1): 179–184.
Article history
Received:
February 19 1996
Revision Received:
May 20 1996
Accepted:
June 19 1996
Citation
Sheree D LONG, Phillip H PEKALA; Lipid mediators of insulin resistance: ceramide signalling down-regulates GLUT4 gene transcription in 3T3-L1 adipocytes. Biochem J 1 October 1996; 319 (1): 179–184. doi: https://doi.org/10.1042/bj3190179
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