The catalytic activity of ceramide synthase 2 regulates transcription of genes involved in lipid metabolism and cell division. Mus musculus

The replacement of two consecutive histidine residues by alanine residues in the catalytic center of ceramide synthase 2 in new transgenic mouse mutants (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 previously described formation of hepatocarcinomas in CerS2 KO mice occurred already in 6‑week-old animals and also originated in the loss of CerS2 catalytic activity. The additional loss of the CerS2 homeodomain in newly generated CerS2 Del mice that almost completely lack CerS2 protein expression mostly corroborated the transcriptional effects of the CerS2 catalytic domain (nevertheless, it appears to have independent effects such as induction of cholangiocarcinomas. Overall design: Whole genome transcript levels were measured in liver total RNA preparations from 16 mice of four different genotypes (four 6-week-old mice per genotype)