Lipase family member N is a novel target gene for CCAAT/enhancer-binding protein α in type 2 diabetic model mouse liver.

CCAAT/enhancer-binding protein α (C/EBPα) is a transcription factor abundantly expressed in the liver and white adipose tissue (WAT). In this study, we investigated the mechanism by which C/EBPα regulates the lipase family member N (Lipn) gene in the mouse liver. Mouse Lipn consists of non-coding exon 1 and the translation start site located in exon 2. Lipn expression in the fatty liver of ob/ob mice was significantly higher than that in OB/OB mice and was significantly repressed by liver-specific C/EBPα deficiency. Lipn expression in ob/ob mice was detected in the liver, epididymal WAT (eWAT), subcutaneous WAT (sWAT), brown adipose tissue (BAT), and skeletal muscle, but not in the kidney, brain, and heart. Lipn expression in the liver, eWAT, and sWAT of wild-type mice was undetectable, although C/EBPα was highly expressed in these tissues. The database analysis revealed four putative C/EBP-responsive elements (CEBPREs), highly homologous with the typical CEBPRE consensus sequence at positions -2,686/-2,678, -1,364/-1,356, -106/-98, and -45/-37 from the transcription start site (+1) of Lipn. Reporter assays using reporter constructs with serial or internal deletions of the 5'-flanking regions of Lipn showed that two functional CEBPREs (-106/-98 and -45/-37) in the Lipn promoter region are essential for enhancing Lipn transcriptional activity by C/EBPα. Electrophoretic mobility shift assay showed that C/EBPα/β binds to CEBPRE (-106/-98). These results suggest that C/EBPα and type 2 diabetic environment may be required for hepatic Lipn expression.