Hepatic Small Ubiquitin-Related Modifier (SUMO)-Specific Protease 2 Controls Systemic Metabolism Through SUMOylation-Dependent Regulation of Liver-Adipose Tissue Crosstalk
Hepatic Small Ubiquitin-Related Modifier (SUMO)-Specific Protease 2 Controls Systemic Metabolism Through SUMOylation-Dependent Regulation of Liver-Adipose Tissue Crosstalk
复制标题
肝脏小泛素相关修饰剂 (SUMO) 特异性蛋白酶 2 通过肝脏-脂肪组织串扰的 SUMO 化依赖性调节来控制全身代谢
DOI：
10.1002/hep.31881
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发表时间：
2021-09-09
期刊：
影响因子：
13.5
通讯作者：
Tang, Qi-Qun
中科院分区：
文献类型：
--
作者：
Liu, Yang;Dou, Xin;Tang, Qi-Qun
背景和目的NAFLD以肝脏甘油三酯异常蓄积为特征，通过分泌肝细胞因子影响肝和非肝组织的代谢重建。小泛素相关修饰物（SUMO）特异性蛋白酶2（SENP 2）负责靶蛋白的去SUMO化，对细胞生长，信号转导和发育过程具有广泛的影响。然而，SENP 2在肝脏代谢中的作用仍不清楚。方法和结果我们发现SENP 2是脂肪肝中最显著增加的SENP，并且其水平受进食/禁食条件的调节。为了确定肝脏SENP 2在代谢调节中的作用，我们产生了肝脏特异性SENP 2敲除（Senp 2-LKO）小鼠。Senp 2-LKO小鼠表现出对高脂饮食诱导的肝脂肪变性和肥胖的抵抗力。RNA测序分析表明，Senp 2缺陷上调参与脂肪酸氧化的基因，下调肝脏脂肪生成的基因。此外，肝SENP 2的消融激活了脂肪组织的产热。通过SENP 2破坏改善肝脏和脂肪组织的能量稳态促使我们检测肝细胞因子，FGF 21被鉴定为在维持代谢稳态的Senp 2-LKO小鼠中显著升高的关键因子。FGF 21的缺失明显逆转了SENP 2缺乏对代谢的积极影响。从机制上讲，通过筛选FGF 21的转录因子，过氧化物酶体增殖物激活受体α（PPAR α）被定义为SENP 2和FGF 21的介导因子。SENP 2与PPAR α相互作用并使其去SUMO化，从而促进PPAR α的泛素化和随后的降解，这反过来又抑制FGF 21表达和脂肪酸氧化。一致地，SENP 2在肝脏中的过表达促进了代谢紊乱的发展。结论我们的发现表明，肝脏SENP 2通过调节肝脏-脂肪组织串扰，将SUMO化过程与代谢调节联系起来，在控制代谢平衡中起关键作用。
Background and Aims NAFLD, characterized by aberrant triglyceride accumulation in liver, affects the metabolic remodeling of hepatic and nonhepatic tissues by secreting altered hepatokines. Small ubiquitin-related modifier (SUMO)-specific protease 2 (SENP2) is responsible for de-SUMOylation of target protein, with broad effects on cell growth, signal transduction, and developmental processes. However, the role of SENP2 in hepatic metabolism remains unclear. Approach and Results We found that SENP2 was the most dramatically increased SENP in the fatty liver and that its level was modulated by fed/fasted conditions. To define the role of hepatic SENP2 in metabolic regulation, we generated liver-specific SENP2 knockout (Senp2-LKO) mice. Senp2-LKO mice exhibited resistance to high-fat diet-induced hepatic steatosis and obesity. RNA-sequencing analysis showed that Senp2 deficiency up-regulated genes involved in fatty acid oxidation and down-regulated genes in lipogenesis in the liver. Additionally, ablation of hepatic SENP2 activated thermogenesis of adipose tissues. Improved energy homeostasis of both the liver and adipose tissues by SENP2 disruption prompted us to detect the hepatokines, with FGF21 identified as a key factor markedly elevated in Senp2-LKO mice that maintained metabolic homeostasis. Loss of FGF21 obviously reversed the positive effects of SENP2 deficiency on metabolism. Mechanistically, by screening transcriptional factors of FGF21, peroxisome proliferator-activated receptor alpha (PPAR alpha) was defined as the mediator for SENP2 and FGF21. SENP2 interacted with PPAR alpha and deSUMOylated it, thereby promoting ubiquitylation and subsequent degradation of PPAR alpha, which in turn inhibited FGF21 expression and fatty acid oxidation. Consistently, SENP2 overexpression in liver facilitated development of metabolic disorders. Conclusions Our finding demonstrated a key role of hepatic SENP2 in governing metabolic balance by regulating liver-adipose tissue crosstalk, linking the SUMOylation process to metabolic regulation.