CRISPR/Cas9-mediated Angptl8 knockout suppresses plasma triglyceride concentrations and adiposity in rats
CRISPR/Cas9-mediated Angptl8 knockout suppresses plasma triglyceride concentrations and adiposity in rats
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DOI：
10.1194/jlr.m082099
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发表时间：
2018-09-01
影响因子：
6.5
通讯作者：
Nakao, Kazuwa
中科院分区：
文献类型：
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作者：
Izumi, Ryota;Kusakabe, Toru;Nakao, Kazuwa
血管生成素样蛋白（ANGPTL）8是一种肝脏和脂肪细胞来源的蛋白质，控制血浆甘油三酯（TG）水平。大多数动物研究使用小鼠模型。在此，我们使用成簇调节间隔短回文重复序列（CRISPR）/CRISPR相关蛋白9（Cas9）（CRISPR/Cas9）系统产生了Angptl 8 KO大鼠模型，以阐明ANGPTL 8在葡萄糖和脂质代谢中的作用。与WT大鼠相比，Angptl 8 KO大鼠的体重和脂肪含量较低，与脂肪细胞中脂肪生成受损相关;各组之间的摄食量或直肠温度无差异。KO大鼠在禁食和再进食状态下的血浆TG水平均显著低于WT大鼠，经口脂肪耐量试验显示Angptl 8 KO大鼠的血浆TG波动降低。在Angptl 8 KO大鼠中观察到心脏中较高水平的脂肪酶活性以及心脏和骨骼肌中与β-氧化相关的基因的较高表达。然而，KO和WT大鼠之间在葡萄糖代谢或胰腺β细胞的组织学方面在标准和高脂饮食中均无显著差异。总之，我们证明了大鼠中Angptl 8 KO导致较低的体重和血浆TG水平，而不影响葡萄糖代谢。ANGPTL 8可能是肥胖和血脂异常的重要治疗靶点。
Angiopoietin-like protein (ANGPTL)8 is a liver- and adipocyte-derived protein that controls plasma triglyceride (TG) levels. Most animal studies have used mouse models. Here, we generated an Angptl8 KO rat model using a clustered regulatory interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein 9 (Cas9) (CRISPR/Cas9) system to clarify the roles of ANGPTL8 in glucose and lipid metabolism. Compared with WT rats, Angptl8 KO rats had lower body weight and fat content, associated with impaired lipogenesis in adipocytes; no differences existed between the groups in food intake or rectal temperature. Plasma TG levels in both the fasted and refed states were significantly lower in KO than in WT rats, and an oral fat tolerance test showed decreased plasma TG excursion in Angptl8 KO rats. Higher levels of lipase activity in the heart and greater expression of genes related to beta-oxidation in heart and skeletal muscle were observed in Angptl8 KO rats. However, there were no significant differences between KO and WT rats in glucose metabolism or the histology of pancreatic beta-cells on both standard and high-fat diets. In conclusion, we demonstrated that Angptl8 KO in rats resulted in lower body weight and plasma TG levels without affecting glucose metabolism. ANGPTL8 might be an important therapeutic target for obesity and dyslipidemia.