Xu Xu, Park Jong-Gil, So Jae-Seon, Lee Ann-Hwee
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY.
Hepatology. 2015 Mar;61(3):857-69. doi: 10.1002/hep.27371. Epub 2015 Jan 28.
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.
脂肪特异性蛋白27（Fsp27）是一种与脂滴相关的蛋白，可促进白色脂肪细胞中脂滴（LD）的生长和甘油三酯（TG）的储存。Fsp27在脂肪变性的肝脏中也高度表达，并促进TG的积累。在本研究中，我们发现肝脏产生Fsp27β，这是一种Fsp27的替代异构体，在原始Fsp27（Fsp27α）的N端含有另外10个氨基酸。白色脂肪组织（WAT）和肝脏分别特异性表达Fsp27α和Fsp27β转录本，它们由不同的启动子驱动。Fsp27β启动子由肝脏富集的转录因子环磷酸腺苷反应元件结合蛋白H（CREBH）激活，而不由激活Fsp27α启动子的过氧化物酶体增殖物激活受体γ（PPARγ）激活。组成型活性CREBH的强制表达分别在小鼠肝细胞和HepG2细胞中强烈诱导Fsp27β和人类同源物CIDEC2。相反，CREBH的缺失降低了禁食小鼠肝脏中的Fsp27β，表明CREBH在肝脏中Fsp27β的表达中起关键作用。与Fsp27α相似，Fsp27β定位于脂滴表面并抑制脂肪分解。因此，Fsp
