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

Yingying Xu,Jiawang Tao,Fan Yang,Jiaye Zhang,Yin-Xiong Li,Yan Chen,Anteneh Getachew,Yuhang Wu,Xianhua Lin,Kai You,Fang Yuan,Tingcai Pan,Yuanqi Zhuang,Xiaorui Yu

doi:10.1172/jci.insight.147038

Abstract

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

Highlights

Dyslipidemia is a major risk factor for the development of metabolic diseases, including fatty liver, type 2 diabetes mellitus, cardiovascular disease (CVD), and stroke
Biochemical analysis of the lipid profile indicated that the whole spectrum of lipids in serum and liver tissues were decreased in asialoglycoprotein receptor 1 (ASGR1)-deficient male mice (Figure 1, C–I)
By detecting SREBP1 and SREBP2, we found that the protein content of nSREBP1 and nSREBP2 was lower in ASGR1-deficient mouse livers and HepG2 cells, while the content of full-length proteins was increased in mice, indicating that the activation was inhibited (Figure 5, A and B)

Summary

Introduction

Dyslipidemia is a major risk factor for the development of metabolic diseases, including fatty liver, type 2 diabetes mellitus, cardiovascular disease (CVD), and stroke. A human population genetic study provided evidence that variant asialoglycoprotein receptor 1 (ASGR1) is associated with lower non–HDL-c content and reduced risk of coronary artery disease (CAD), indicating a potential target for CVD prevention and treatment [3]. ASGR functions as a C-type lectin mediating endocytosis and degradation of desialylated proteins in circulation [5]. It plays a pivotal role in a variety of pathophysiologic processes, such as removal of desialylated platelets [6, 7], suppression of hepatocellular carcinoma metastasis [8], elimination of activated lymphocytes [9], and serving as the gate for hepatotropic viruses [10, 11]. With support of the population genetic study data, ASGR1 is emerging as an attractive protein for dissecting the regulatory network of lipid homeostasis and a potential target for lipid-lowering drug development

Methods

Results

Conclusion