Yin Yunjun, Liu Jun, Yu Jia, Dong Dingcai, Gao Fei, Yu Libao, Du Xuguang, Wu Sen
State Key Laboratory of Animal Biotech Breeding, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
Sanya Institute of China Agricultural University, Sanya 572024, China.
iScience. 2024 Jun 17;27(7):110288. doi: 10.1016/j.isci.2024.110288. eCollection 2024 Jul 19.
Although the role of asialoglycoprotein receptor 1 (ASGR1) in lowering lipid levels is well established, recent studies indicate that ASGR1 inhibition can cause unexpected liver damage in pigs, raising a serious issue about whether ASGR1 can be a good target for treating ASCVD. Here, we utilized the CRISPR-Cas9 system to regenerate ASGR1-knockout pigs, who displayed decreased lipid profiles without observable liver damage. This was confirmed by the lower levels of serum ALT and AST, reduced expression of inflammation markers, and normal histological morphology. Also, we implemented immunoprecipitation combined with mass spectrometry (IP-MS) and discovered that paraoxonase-2 (PON2) can interact with and significantly degrade ASGR1 in a dose-dependent manner. This degradation reduced lipid levels in mice, accompanied by little inflammation. Our study highlights the effectiveness and safety of degrading ASGR1 to reduce lipid levels in pigs and provides a potential inhibitor of ASGR1.
尽管去唾液酸糖蛋白受体1（ASGR1）在降低血脂水平方面的作用已得到充分证实，但最近的研究表明，抑制ASGR1会在猪身上导致意想不到的肝损伤，这引发了一个严重问题，即ASGR1是否可成为治疗动脉粥样硬化性心血管疾病（ASCVD）的良好靶点。在此，我们利用CRISPR-Cas9系统培育出ASGR1基因敲除猪，这些猪的血脂水平降低，且未观察到肝损伤。血清谷丙转氨酶（ALT）和谷草转氨酶（AST）水平降低、炎症标志物表达减少以及组织形态学正常证实了这一点。此外，我们进行了免疫沉淀结合质谱分析（IP-MS），发现对氧磷酶-2（PON2）可与ASGR1相互作用，并以剂量依赖的方式显著降解ASGR1。这种降解降低了小鼠的血脂水平，且几乎没有炎症反应。我们的研究突出了降解ASGR1以降低猪血脂水平的有效性和安全性，并提供了一种潜在的ASGR1抑制剂。
