Transcriptional activation of Fsp27 by the liver-enriched transcription factor CREBH promotes lipid droplet growth and hepatic steatosis.

Fat-specific protein 27 (Fsp27) is a lipid droplet-associated protein that promotes lipid droplet (LD) growth and triglyceride (TG) storage in white adipocytes. Fsp27 is also highly expressed in the steatotic liver and contributes to TG accumulation. In this study we discovered that the liver produces Fsp27β, an alternative Fsp27 isoform, which contains 10 additional amino acids at the N-terminus of the original Fsp27 (Fsp27α). White adipose tissue (WAT) and the liver specifically expressed Fsp27α and Fsp27β transcripts, respectively, which were driven by distinct promoters. The Fsp27β promoter was activated by the liver-enriched transcription factor cyclic-AMP-responsive-element-binding protein H (CREBH) but not by peroxisome proliferator-activated receptor gamma (PPARγ), which activated the Fsp27α promoter. Enforced expression of the constitutively active CREBH strongly induced Fsp27β and the human ortholog CIDEC2 in mouse hepatocytes and HepG2 cells, respectively. In contrast, loss of CREBH decreased hepatic Fsp27β in fasted mice, suggesting that CREBH plays a critical role in Fsp27β expression in the liver. Similar to Fsp27α, Fsp27β localized on the surface of lipid droplets and suppressed lipolysis. Consequently, enforced expression of Fsp27β or CREBH promoted lipid droplet enlargement and TG accumulation in the liver. The CREBH-Fsp27β axis is important for regulating lipid droplet dynamics and TG storage in the liver.