ANGPTL3: A liver-derived protein that plays a crucial role in regulating lipid metabolism.

• Gene Information: Angiopoietin-like 3, also known as ANGPTL3, is a protein encoded by the ANGPTL3 gene in humans, as a member of the angiopoietin-like family of secreted factors
•  Protein Expression: ANGPTL3 is a liver-derived glycoprotein that exerts inhibitory effects on both lipoprotein lipase and endothelial lipase.
•  Signaling Pathway: ANGPTL3, also referred to as angiopoietin-like protein 3, is a liver-derived protein with critical functions in lipid-metabolism regulation. It modulates the activity of lipoprotein lipase (LPL), the enzyme responsible for triglyceride hydrolysis in circulating blood. By suppressing LPL function, ANGPTL3 increases circulating concentrations of triglycerides, low-density lipoprotein (LDL)-cholesterol, and high-density lipoprotein (HDL)-cholesterol.
• Therapeutic Method: Clinical trials have shown that ANGPTL3 inhibitors can markedly lower circulating LDL-cholesterol, triglyceride, and HDL-cholesterol concentrations, representing a promising therapeutic option for patients with refractory hyperlipidemia.

B-hANGPTL3 mice ad

•  The BAC containing the whole human ANGPTL3 genome sequence, including human promoter, 5’UTR, and 3’UTR were randomly inserted into the B-hANGPTL3 mice plus.
• The human ANGPTL3 expression is driven by the human ANGPTL3 promoter.
•  The mouse Angptl3 gene transcription and translation will be disrupted.

B-hANGPTL3 mice plus

•  The genome of the mouse Angptl3 gene, including 5’UTR and 3’UTR, was replaced by the human ANGPTL3 genome, including 5’UTR and 3’UTR in B-hANGPTL3 mice plus.
•  The 5’UTR and 3’UTR region of the mouse gene were also be replaced by human 5’UTR and 3’UTR.
•  The mouse Angptl3 gene transcription and translation will be disrupted.

Strain specific ANGPTL3 expression analysis in wild-type C57BL/6JNifdc mice and B-hANGPTL3 mice ad by ELISA. Serum was collected from wild-type C57BL/6JNifdc mice (+/+) (male, n=3, 8-week-old) and F3 B-hANGPTL3 mice ad (Tg, H/H) (male, n=6; female, n=3, 8-week-old). Expression level of human ANGPTL3 was analyzed by ELISA (human ANGPTL3 ELISA kit: R&D Systems, DANL30). Human ANGPTL3 was exclusively detectable in F3 B-hANGPTL3 mice ad. Values are expressed as mean ± SEM. (Fasting 6 hours before blood collection).

The inhibitory efficiency of the nucleic acid drugs against human ANGPTL3 in B-hANGPTL3 mice ad. B-hANGPTL3 mice ad (Tg, H/H) were randomly divided into two groups (male, 9-week-old). The human ANGPTL3 targeted nucleic acid drugs (synthesized according to patents), and PBS were administered to the mice individually. The nucleic acid drug was administered in the form of a PBS aqueous solution. (A) The schematic diagram of experimental processing. (B) Expression level of human ANGPTL3 was analyzed by ELISA (human ANGPTL3 ELISA kit: R&D Systems, DANL30). (C) Triglyceride (TG) in serum after treatment. Values are expressed as mean ± SEM. (Fasting 6 hours before blood collection).

In vivo efficacy of Western Diet (WD)-induced B-hANGPTL3 mice ad. B-hANGPTL3 mice ad were fed with Western Diet (XT079B, 40% energy from fat and 0.15% cholesterol) and were divided into two groups according to the LDL-C. ARO-ANG3-analog (MCE, HY-177671) were administered to the mice individually.

In vivo efficacy of WD-induced B-hANGPTL3 mice ad. B-hANGPTL3 mice ad were fed with Western Diet (XT079B, 40% energy from fat and 0.15% cholesterol) and were divided into two groups according to the LDL-C. ARO-ANG3-analog (MCE, HY-177671) were administered to the mice individually. (A) LDL-C change after treatment. (B) TG change after treatment. Values are expressed as mean ± SEM. WD: Western Diet. (Fasting 6 hours before blood collection).