Inactivation of ceramide synthase 2 catalytic activity in mice affects transcription of genes involved in lipid metabolism and cell division

The replacement of two consecutive histidine residues by alanine residues in the catalytic center of ceramide synthase 2 in a new transgenic mouse mutant (CerS2 H/A) leads to inactivation of catalytic activity and reduces protein level to 60% of the WT level. We show here by qRT-PCR and transcriptom...

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Bibliographic Details
Published in:Biochimica et biophysica acta. Molecular and cell biology of lipids 2018-07, Vol.1863 (7), p.734-749
Main Authors: Bickert, Andreas, Kern, Paul, van Uelft, Martina, Herresthal, Stefanie, Ulas, Thomas, Gutbrod, Katharina, Breiden, Bernadette, Degen, Joachim, Sandhoff, Konrad, Schultze, Joachim L., Dörmann, Peter, Hartmann, Dieter, Bauer, Reinhard, Willecke, Klaus
Format: Article
Language:English
Subjects:
Age Factors
Animals
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - pathology
Cell division
Cell Division - genetics
Ceramide synthase 2
Ceramides - metabolism
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Hepatocellular carcinoma
Lipid metabolism
Lipid Metabolism - genetics
Liver - pathology
Liver Neoplasms - genetics
Liver Neoplasms - pathology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mutation
Sphingolipids
Sphingosine N-Acyltransferase - genetics
Sphingosine N-Acyltransferase - metabolism
Transcriptional control
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Summary:The replacement of two consecutive histidine residues by alanine residues in the catalytic center of ceramide synthase 2 in a new transgenic mouse mutant (CerS2 H/A) leads to inactivation of catalytic activity and reduces protein level to 60% of the WT level. We show here by qRT-PCR and transcriptome analyses that several transcripts of genes involved in lipid metabolism and cell division are differentially regulated in livers of CerS2 H/A mice. Thus, very long chain ceramides produced by CerS2 are required for transcriptional regulation of target genes. The hepatocellular carcinomata previously described in old CerS2 KO mice were already present in 8-week-old CerS2 H/A animals and thus are caused by the loss of CerS2 catalytic activity already during early life. •Very long chain ceramides generated by CerS2 exert transcriptional control.•Hepatic lipid metabolism is stabilized by CerS2 catalytic activity.•Formation of hepatocellular carcinomata is initiated upon inactivation of CerS2.
ISSN:1388-1981
1879-2618
DOI:10.1016/j.bbalip.2018.04.006