huANGPTL3/huPCSK9 Mouse

Angiopoietin‑like protein 3 (ANGPTL3) is mainly expressed in the liver and is a secreted glycoprotein structurally related to angiopoietins. The mature form of human ANGPTL3 protein contains an N‑terminal coiled‑coil domain and a C‑terminal fibrinogen‑like (FBN) domain. Through binding of its FBN‑like domain to integrin αvβ3, ANGPTL3 induces endothelial cell adhesion and migration, thereby playing a role in the regulation of angiogenesis ^[1]. In addition, ANGPTL3 can directly inhibit lipoprotein lipase (LPL) and endothelial lipase (EL), which are closely involved in the hydrolysis of circulating triglycerides (TG) and high‑density lipoprotein cholesterol (HDL‑C), respectively, thereby elevating circulating TG levels and affecting HDL levels ^[2-3]. In humans, ANGPTL3 is an important factor for HDL levels, and its plasma level is positively correlated with HDL‑C. Loss‑of‑function mutations in the ANGPTL3 gene (especially homozygous or compound heterozygous) lead to familial combined hypolipidemia (FHBL2) ^[4]. Furthermore, ANGPTL3 also plays important roles in biological and pathological processes related to lipid metabolism and angiogenesis, such as atherosclerosis, tumors, nephrotic syndrome, diabetes, and liver disease ^[3].

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease produced predominantly in the liver and also expressed in the intestine, heart, pancreas, renal interstitial cells, and neurons. The N-terminal and catalytic domains of PCSK9 are involved in protein maturation and stability, while the C-terminal domain plays a critical role in LDLR degradation ^[5]. PCSK9 is closely involved in the regulation of blood cholesterol. The low‑density lipoprotein receptor (LDLR) is a receptor responsible for clearing low‑density lipoprotein cholesterol (LDL‑C); PCSK9 binds to the EGF-A domain of cell-surface LDLR, promoting its endocytosis and lysosomal degradation, thereby reducing LDLR levels and elevating plasma LDL-C. Overexpression or gain‑of‑function mutations of the PCSK9 gene reduce LDLR levels, resulting in LDL‑C accumulation, hypercholesterolemia, and increased risks of cardiovascular diseases such as atherosclerosis and coronary heart disease, as well as neurodegenerative disorders including stroke and Alzheimer's disease ^[6].

The huANGPTL3/huPCSK9 mouse is a dual humanized model generated by gene editing on the huPCSK9 mouse (Catalog No.: C001617) background, in which the mouse Angptl3 endogenous region from the p.S17 to downstream of Exon 7 was replaced with the human ANGPTL3 region from p.S17 to downstream of Exon 7. The murine signal peptide was retained. This model is applicable to mechanistic studies of metabolic diseases, such as hypertriglyceridemia, hypercholesterolemia, and dyslipidemia, and is also suitable for the screening, development, and preclinical evaluation of dual-targeting drugs against ANGPTL3 and PCSK9.