QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jpet.108.139394v1 326/3/849    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bijl, N. Articles by Aerts, J. M. F. G. Search for Related Content PubMed PubMed Citation Articles by Bijl, N. Articles by Aerts, J. M. F. G.

CELLULAR AND MOLECULAR

The Glucosylceramide Synthase Inhibitor N-(5-Adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin Induces Sterol Regulatory Element-Binding Protein-Regulated Gene Expression and Cholesterol Synthesis in HepG2 Cells

Departments of Medical Biochemistry (N.B., S.S., R.G.B., A.K.G., J.M.F.G.A.) and Clinical Chemistry, Laboratory Genetic Metabolic Diseases (S.H.), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Recent findings have implicated glycosphingolipids as modulators of insulin receptor activity. Studies with C57BL/6J ob/ob mice have shown that insulin sensitivity is enhanced by the synthetic hydrophobic iminosugar N-(5-adamantane-1-yl-methoxy-pentyl)-deoxynojirimycin (AMP-DNM) that inhibits glucosylceramide synthase. Here, we treated the liver hepatoma cell line HepG2 with AMP-DNM, resulting in a 70% reduction of glycosphingolipids, and we analyzed the effect on gene expression. Using whole human genome 44K oligonucleotide arrays, we identified 89 genes that were significantly (p < 0.01) up- or down-regulated by AMP-DNM treatment. Of the 56 up-regulated genes, 17 were direct target genes for transcription factors sterol regulatory element-binding protein (SREBP) 1 or SREBP2, which activate genes in the sterol biosynthesis pathway. An increase in cholesterol production rate confirmed that the induction of SREBP target genes seen at the mRNA level resulted in activation of the cholesterol biosynthesis pathway. It is interesting to note that the cholesterol content of the cells did not increase. It is noteworthy that no effects were found on expression of genes related to cell receptor signaling pathways, neither on toxicity nor cell growth. Our findings indicate that inhibition of glucosylceramide synthase with AMP-DNM leads to activation of SREBP target genes and synthesis of cholesterol in HepG2 cells.

Address correspondence to: Dr. Rolf G. Boot, Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands. E-mail: r.g.boot{at}amc.uva.nl

This article has been cited by other articles:

				P. Giussani, L. Brioschi, R. Bassi, L. Riboni, and P. Viani Phosphatidylinositol 3-Kinase/AKT Pathway Regulates the Endoplasmic Reticulum to Golgi Traffic of Ceramide in Glioma Cells: A LINK BETWEEN LIPID SIGNALING PATHWAYS INVOLVED IN THE CONTROL OF CELL SURVIVAL J. Biol. Chem., February 20, 2009; 284(8): 5088 - 5096. [Abstract] [Full Text] [PDF]