B6-hPCSK9/TG-hAPOC3 Mouse

Proprotein convertase subtilisin/kexin 9 (PCSK9) is a serine protease primarily produced in the liver but expressed in other tissues, including the intestine, heart, and neurons. The N-terminal domain of the PCSK9 protein is responsible for protein localization and stability, while the C-terminal domain is responsible for protein enzymatic activity ^[1]. The Low-density lipoprotein receptor (LDLR) is a receptor that is responsible for clearing low-density lipoprotein cholesterol (LDL-C) from the blood. PCSK9 cleaves the intracellular domain of LDLR on the cell surface, causing it to detach from the cell membrane and be transported to the lysosome for degradation, promoting LDLR degradation, and increasing plasma LDL-C. Overexpression or gain-of-function mutations of the PCSK9 gene can lead to LDL-C accumulation by reducing LDLR levels. This can cause hypercholesterolemia, which increases the risk of cardiovascular diseases, such as atherosclerosis and coronary heart disease, and neurodegenerative diseases, such as Alzheimer's disease ^[2]. PCSK9 has become an important target for the development of lipid-lowering drugs. Several PCSK9-targeted antibodies or small nucleic acid drugs have been approved for marketing worldwide, including evolocumab from Amgen, alirocumab from Sanofi and Regeneron, and inclisiran from Novartis. These drugs primarily work by inhibiting PCSK9 activity or preventing PCSK9 protein from binding to LDLR, lowering LDL-C levels in the blood to treat hypercholesterolemia ^[3-4]. In addition, PCSK9 can promote tumor growth and development by regulating cell proliferation, migration, and invasion. It can also regulate the expression of inflammatory factors that contribute to inflammation. Therefore, targeting the expression of PCSK9 has been investigated in tumor immunotherapy and autoimmune disease therapy ^[5-6].

Apolipoprotein C-III (ApoC-III), encoded by the APOC3 gene, is a 79-amino acid glycoprotein primarily synthesized in the liver, with minor production in the intestine. ApoC-III is a key component of triglyceride-rich lipoproteins (TRLs), including chylomicrons and very low-density lipoprotein (VLDL). Its primary functions include inhibiting lipoprotein lipase (LPL)-mediated hydrolysis of triglycerides within TRLs and modulating hepatic uptake of TRL remnants, thereby elevating plasma triglyceride levels. Consequently, ApoC-III is crucial in regulating plasma triglyceride levels ^[7-8]. Elevated APOC3 expression leads to increased ApoC-III levels, which is associated with hypertriglyceridemia (a risk factor for cardiovascular disease) and conditions such as familial hypertriglyceridemia, metabolic syndrome, and type 2 diabetes. Therefore, targeting the reduction of APOC3 expression or blocking its protein function offers a therapeutic avenue for hypertriglyceridemia and mitigating cardiovascular disease risk ^[9].

B6-hPCSK9/TG-hAPOC3 mice are humanized models generated by crossing B6-hPCSK9 mice (Catalog No.: C001617) with TG-hAPOC3 mice (Catalog No.: C001588), enabling systemic expression of human PCSK9 and ApoC-Ⅲ proteins. This model is suitable for developing drugs targeting human APOC3/PCSK9, such as small interfering RNA (siRNA) and antisense oligonucleotides (ASO), for treating hypertriglyceridemia and other metabolic disorders, as well as for research on neurodegenerative diseases, tumorigenesis, and autoimmune diseases.