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Cyclic AMP Response Element-Binding Protein 1 ( Creb1 ) is a transcription factor that mediates cyclic adenosine 3′, 5′-monophosphate (cAMP) signalling in many tissues.  Creb1 −/−   mice die at birth due to respiratory failure and previous genome-wide microarray analysis of E17.5  Creb1 −/−   fetal mouse lung identified important Creb1-regulated gene targets during lung development. The lipogenic enzymes stearoyl-CoA desaturase 1 ( Scd1 ) and fatty acid synthase ( Fasn ) showed highly reduced gene expression in  Creb1 −/−   lungs. We therefore hypothesized that Creb1 plays a crucial role in the transcriptional regulation of genes involved in pulmonary lipid biosynthetic pathways during lung development. In this study we confirmed that  Scd1  and  Fasn  mRNA levels were down regulated in the E17.5  Creb1 −/−   mouse lung while the lipogenic-associated transcription factors  SrebpF1 ,  C/ebpα  and  Pparγ  were increased.  In vivo  studies using germline ( Creb1 −/−  ) and lung epithelial-specific ( Creb1 EpiΔ/Δ  ) Creb1 knockout mice showed strongly reduced Scd1, but not Fasn gene expression and protein levels in lung epithelial cells.  In vitro  studies using mouse MLE-15 epithelial cells showed that forskolin-mediated activation of Creb1 increased both  Scd1  gene expression and protein synthesis. Additionally, MLE15 cells transfected with a dominant-negative ACreb vector blocked forskolin-mediated stimulation of  Scd1  gene expression. Lipid profiling in MLE15 cells showed that dominant-negative  ACreb  suppressed forskolin-induced desaturation of ether linked lipids to produce plasmalogens, as well as levels of phosphatidylethanolamine, ceramide and lysophosphatidylcholine. Taken together these results demonstrate that  Creb1  is essential for the induction and maintenance of  Scd1  in developing fetal mouse lung epithelial cells.

cAMP Response Element Binding Protein1 Is Essential for Activation of Steroyl Co-Enzyme A Desaturase 1 (Scd1) in Mouse Lung Type II Epithelial Cells