Yang Zhou, Sun Jian, Ji Hong, Shi Xiao-Chen, Li Yang, Du Zhen-Yu, Chen Li-Qiao
College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China.
College of Animal Science and Technology, Northwest A&F University, Yangling 712100, China.
Dev Comp Immunol. 2017 Jun;71:8-17. doi: 10.1016/j.dci.2017.01.016. Epub 2017 Jan 19.
Pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNFα), may contribute to hepatic steatosis in the situation of excess lipid accumulation in farmed fish. Pigment epithelium-derived factor (PEDF) is an endogenous anti-inflammatory factor and promotes lipolysis. Accordingly, we isolated PEDF from grass carp and investigated its role in TNFα-induced hepatic steatosis. Sequence analysis showed that PEDF gene, which possesses 8 exons and 7 introns, encodes a protein with 409 amino acids. PEDF was a critical determinant of the transcriptional response to nutrient availability in grass carp. Endogenous PEDF was an intracellular protein with cytoplasmic distribution and directly interacts with adipose triglyceride lipase (ATGL), which might mediate PEDF-induced lipolysis. TNFα significantly promoted lipid accumulation in vivo and in vitro, accompanied with a decrease in mRNA levels of PEDF and peroxisome proliferator-activated receptor alpha (PPARα). Recombinant PEDF and PPARα agonist diminished the TNFα-induced hepatic steatosis. Meanwhile, PPARα agonist caused an increase in PEDF expression, suggesting that TNFα antagonizes the actions of PEDF possibly in a PPARα-dependent manner. These findings suggest that PEDF is an important protective factor against hepatic steatosis induced by TNFα, which provided a new therapeutic target for inflammation-associated hepatic steatosis.
促炎细胞因子，如肿瘤坏死因子α（TNFα），在养殖鱼类脂质过度积累的情况下可能导致肝脏脂肪变性。色素上皮衍生因子（PEDF）是一种内源性抗炎因子，可促进脂肪分解。因此，我们从草鱼中分离出PEDF，并研究了其在TNFα诱导的肝脏脂肪变性中的作用。序列分析表明，PEDF基因有8个外显子和7个内含子，编码一种含409个氨基酸的蛋白质。PEDF是草鱼对营养物质可利用性转录反应的关键决定因素。内源性PEDF是一种分布于细胞质的细胞内蛋白质，直接与脂肪甘油三酯脂肪酶（ATGL）相互作用，这可能介导PEDF诱导的脂肪分解。TNFα在体内和体外均显著促进脂质积累，同时PEDF和过氧化物酶体增殖物激活受体α（PPARα）的mRNA水平降低。重组PEDF和PPARα激动剂减轻了TNFα诱导的肝脏脂肪变性。同时，PPARα激动剂使PEDF表达增加，表明TNFα可能以PPARα依赖的方式拮抗PEDF的作用。这些发现表明，PEDF是抵抗TNFα诱导的肝脏脂肪变性的重要保护因子，为炎症相关的肝脏脂肪变性提供了新的治疗靶点。
