B6J-hANGPTL3 Mice

Catalog Number: C001400

Genetic Background: C57BL/6JCya

Reproduction: Homozygote x Homozygote

Strain Description

Angiopoietin-like 3 encoded by the ANGPTL3 gene is a member of the angiopoietin-like secretory growth factor family. The protein is mainly expressed in the liver and is a secreted glycoprotein related to angiopoietin structure. Mature human ANGPTL3 protein contains an N-terminal coiled-coil domain and a C-terminal fibrinogen (FBN)-like domain. The protein induces endothelial cell adhesion and migration by binding the FBN-like domain to integrin α5β3 and plays a role in regulating angiogenesis ^[1]. ANGPTL3 can directly inhibit lipoprotein lipase (LPL) and endothelial lipase (EL) which are closely related to the hydrolysis of circulating triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C). It can increase the level of circulating TG without changing the secretion or uptake of very low-density lipoprotein (VLDL) or HDL ^[2]. ANGPTL3 is a key determinant of HDL levels and is positively correlated with high-density lipoprotein cholesterol (HDL-C) in plasma. Loss-of-function mutations in the ANGPTL3 gene can lead to familial combined hyperlipidemia (FCH) ^[3]. In addition, ANGPTL3 plays a crucial role in biological or pathological processes related to lipid metabolism, angiogenesis, and hematopoiesis, such as atherosclerosis, carcinogenesis, nephrotic syndrome, diabetes, and liver disease ^[4].

This strain is a mouse Angptl3 gene humanized model. The mouse Angptl3 gene is replaced with the human ANGPTL3 gene sequence by gene editing technology, which expresses the human ANGPTL3 protein while retaining the signal peptide of mouse Angptl3. This model can be used to study the pathogenesis of metabolic diseases such as atherosclerosis, diabetes, and familial combined hyperlipidemia (FCH), as well as the development and screening of ANGPTL3-targeted drugs. The homozygous B6J-hANGPTL3 mice are viable and fertile.

Strain Strategy

Figure 1. The gene editing strategy for generating B6J-hANGPTL3 mice. The mouse endogenous region from p.S17 to ~1 kb downstream of Exon 7 was replaced with the human ANGPTL3 region from p.S17 to ~1 kb downstream of Exon 7. The murine signal peptide (aa.1~16) was remained.

Validation Data

1. Detection of ANGPTL3 gene in the liver by QPCR

Figure 2. The expression of human ANGPTL3 gene in the liver tissue of wild-type mice (C57BL/6) and B6J-hANGPTL3 mice. The results showed that human ANGPTL3 gene expression was present in the liver of B6J-hANGPTL3 mice.

 

2. Detection of human ANGPTL3 protein in serum by ELISA

Figure 3. The expression of human ANGPTL3 protein in the serum of B6J-hANGPTL3 mice. The results showed that compared with wild-type mice (C57BL/6), there was a strong expression of human ANGPTL3 protein in B6J-hANGPTL3 mice.

Reference

[1] Conklin D, Gilbertson D, Taft DW, Maurer MF, Whitmore TE, Smith DL, Walker KM, Chen LH, Wattler S, Nehls M, Lewis KB. Identification of a mammalian angiopoietin-related protein expressed specifically in liver. Genomics. 1999 Dec 15;62(3):477-82.

[2] Akoumianakis I, Zvintzou E, Kypreos K, Filippatos TD. ANGPTL3 and Apolipoprotein C-III as Novel Lipid-Lowering Targets. Curr Atheroscler Rep. 2021 Mar 10;23(5):20.

[3] Musunuru K, Pirruccello JP, Do R, Peloso GM, Guiducci C, Sougnez C, Garimella KV, Fisher S, Abreu J, Barry AJ, Fennell T, Banks E, Ambrogio L, Cibulskis K, Kernytsky A, Gonzalez E, Rudzicz N, Engert JC, DePristo MA, Daly MJ, Cohen JC, Hobbs HH, Altshuler D, Schonfeld G, Gabriel SB, Yue P, Kathiresan S. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 2010 Dec 2;363(23):2220-7.

[4] Mohamed F, Mansfield BS, Raal FJ. ANGPTL3 as a Drug Target in Hyperlipidemia and Atherosclerosis. Curr Atheroscler Rep. 2022 Dec;24(12):959-967.