ANGPTL3, short for angiopoietin-like protein 3, is a multifunctional secreted protein mainly expressed in the liver [3]. It belongs to a family of proteins that play a crucial role in lipid metabolism by inhibiting lipoprotein lipase and other lipases, often via forming a complex with ANGPTL8 [1,4]. Additionally, ANGPTL3 is involved in multiple signaling pathways such as LXR/ANGPTL3, thyroid hormone/ANGPTL3, insulin/ANGPTL3 and leptin/ANGPTL3, which are associated with various physiological and pathological processes [3].

Large-scale genetic studies in humans have shown that carriers of loss-of-function variants in ANGPTL3 have lower plasma LDL-C and triglyceride levels, and are at reduced risk of atherosclerotic cardiovascular disease [1,5]. In dyslipidemic mice, inhibition of Angptl3 with evinacumab led to a greater decrease in atherosclerotic lesion area and necrotic content compared to a control antibody [5]. Clinical studies in patients with different forms of dyslipidemia, including homozygous familial hypercholesterolemia and hypertrygliceridemic patients, have demonstrated that inactivation of ANGPTL3 using monoclonal antibodies, antisense oligonucleotides, or RNA interference therapies can markedly lower plasma LDL-C and triglyceride levels [1,2,6,7,8,9].

In conclusion, ANGPTL3 is a key regulator in lipid metabolism. Findings from loss-of-function studies in both humans and mice have revealed its significant role in reducing the risk of atherosclerotic cardiovascular disease by lowering lipid levels. These insights have provided a strong rationale for developing ANGPTL3-targeting therapies for treating dyslipidemia and related cardiovascular diseases [1,2,5,7,8].

References:

1. Kersten, Sander. . ANGPTL3 as therapeutic target. In Current opinion in lipidology, 32, 335-341. doi:10.1097/MOL.0000000000000789. https://pubmed.ncbi.nlm.nih.gov/34581310/

2. Bini, Simone, Tramontano, Daniele, Minicocci, Ilenia, D'Erasmo, Laura, Arca, Marcello. 2023. How ANGPTL3 Inhibition Will Help Our Clinical Practice? In Current atherosclerosis reports, 25, 19-29. doi:10.1007/s11883-022-01076-w. https://pubmed.ncbi.nlm.nih.gov/36607583/

3. Jiang, Shuang, Qiu, Guo-Hui, Zhu, Neng, Liao, Duan-Fang, Qin, Li. 2019. ANGPTL3: a novel biomarker and promising therapeutic target. In Journal of drug targeting, 27, 876-884. doi:10.1080/1061186X.2019.1566342. https://pubmed.ncbi.nlm.nih.gov/30615486/

4. Sylvers-Davie, Kelli L, Davies, Brandon S J. 2021. Regulation of lipoprotein metabolism by ANGPTL3, ANGPTL4, and ANGPTL8. In American journal of physiology. Endocrinology and metabolism, 321, E493-E508. doi:10.1152/ajpendo.00195.2021. https://pubmed.ncbi.nlm.nih.gov/34338039/

5. Dewey, Frederick E, Gusarova, Viktoria, Dunbar, Richard L, Gromada, Jesper, Baras, Aris. 2017. Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. In The New England journal of medicine, 377, 211-221. doi:10.1056/NEJMoa1612790. https://pubmed.ncbi.nlm.nih.gov/28538136/

6. Rosenson, Robert S, Gaudet, Daniel, Hegele, Robert A, Hellawell, Jennifer, Watts, Gerald F. 2024. Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia. In The New England journal of medicine, 391, 913-925. doi:10.1056/NEJMoa2404147. https://pubmed.ncbi.nlm.nih.gov/38809174/

7. Luo, Fei, Das, Avash, Khetarpal, Sumeet A, Rosenson, Robert S, Qamar, Arman. 2023. ANGPTL3 inhibition, dyslipidemia, and cardiovascular diseases. In Trends in cardiovascular medicine, 34, 215-222. doi:10.1016/j.tcm.2023.01.008. https://pubmed.ncbi.nlm.nih.gov/36746257/

8. Mohamed, Farzahna, Mansfield, Brett S, Raal, Frederick J. 2022. ANGPTL3 as a Drug Target in Hyperlipidemia and Atherosclerosis. In Current atherosclerosis reports, 24, 959-967. doi:10.1007/s11883-022-01071-1. https://pubmed.ncbi.nlm.nih.gov/36367663/

9. Tomlinson, Brian, Wu, Qian-Yan, Zhong, Yi-Ming, Li, Yan-Hong. 2023. Advances in Dyslipidaemia Treatments: Focusing on ApoC3 and ANGPTL3 Inhibitors. In Journal of lipid and atherosclerosis, 13, 2-20. doi:10.12997/jla.2024.13.1.2. https://pubmed.ncbi.nlm.nih.gov/38299167/