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 alpha (C/EBP alpha) is a transcription factor abundantly expressed in the liver and white adipose tissue (WAT). In this study, we investigated the mechanism by which C/EBP alpha 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/EBP alpha deficiency. Lipn expression in ob/ob mice was detected in the liver, epididymal wAr (ewAr), 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/EBP alpha was highly expressed in these tissues. The database analysis revealed four putative CIEBP-responsive elements (CEBPREs), highly homologous with the typical CEBPRE consensus sequence at positions -2,6861-2,678, -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/EBP alpha. Electrophoretic mobility shift assay showed that C/EBP alpha/beta binds to CEBPRE (-106/-98). These results suggest that C/EBP alpha and type 2 diabetic environment may be required for hepatic Lipn expression.

Automated summary

CCAAT/enhancer-binding protein alpha (C/EBP alpha) is a transcription factor abundantly expressed in the liver and white adipose tissue (WAT). This study investigates the mechanism by which C/EBP alpha regulates the lipase family member N (Lipn) gene in the mouse liver. The results suggest that C/EBP alpha and type 2 diabetic environment may be required for hepatic Lipn expression. Two functional CEBPREs in the Lipn promoter region are essential for enhancing Lipn transcriptional activity by C/EBP alpha.