Hypomorphic ASGR1 modulates lipid homeostasis via INSIG1-mediated SREBP signaling suppression

• DOI: 10.1172/jci.insight.147038
• Publication Date: 2021-10-07T18:02:20Z
• Authors: Yingying Xu; Jiawang Tao; Xiaorui Yu; Yuhang Wu; Yan Chen; Kai You; Jiaye Zhang; Anteneh Getachew; Tingcai Pan; Yuanqi Zhuang; Fang Yuan; Fan Yang; Xianhua Lin; Yin-xiong Li
• Keywords: PCSK9

A population genetic study identified that the asialoglycoprotein receptor 1 (ASGR1) mutation carriers had substantially lower non–HDL-cholesterol (non–HDL-c) levels and reduced risks of cardiovascular diseases. However, mechanism behind this phenomenon remained unclear. Here, we established Asgr1-knockout mice represented a plasma lipid profile with significantly non–HDL-c triglyceride (TG) caused by decreased secretion increased uptake VLDL/LDL. These 2 phenotypes were linked expression microsomal transfer protein proprotein convertase subtilisin/kexin type 9, key targeted genes sterol regulatory element–binding proteins (SREBPs). Furthermore, there fewer nuclear SREBPs (nSREBPs) on account more being trapped in endoplasmic reticulum, which was an insulin-induced gene (INSIG1), anchor SREBPs. Overexpression knockdown interventions, different models, conducted to rescue ASGR1-deficient phenotypes, found INSIG1 independently reversed ASGR1-mutated serum total cholesterol, LDL-c, TG, liver cholesterol content accompanied restored SREBP signaling. ASGR1 experiments network defect as manifested improved apolipoprotein B LDL uptake. Our observation demonstrated is critical factor responsible for deficiency–associated changes nSREBP suppression. This finding ASGR1/INSIG1/SREBP axis regulating hemostasis may provide multiple potential targets lipid-lowering drug development.