Apoa5, encoding apolipoprotein AV, is a gene with a crucial function in plasma triglyceride (TG) metabolism [1,2,3,4,5]. It is almost exclusively expressed in the liver, and its product apoAV has a very low circulating concentration [2]. Apoa5 functions by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8), suppressing its ability to inhibit lipoprotein lipase (LPL) catalytic activity and detach LPL from binding sites within capillaries, thus regulating TG levels [1,3,5].

Apoa5 -/- mouse models have been instrumental in revealing its role [1,3]. In these mice, Apoa5 deficiency leads to hypertriglyceridemia due to increased ANGPTL3/8 activity and lower LPL activity, as well as reduced amounts of LPL in capillaries of oxidative tissues like the heart and brown adipose tissue [1]. Recombinant Apoa5 can normalize both low intracapillary LPL levels and high plasma TG levels in Apoa5 -/- mice [1]. Also, a mutant Apoa5 lacking 40-carboxyl-terminal residues cannot bind to ANGPTL3/8 and fails to change intracapillary LPL levels or plasma TG levels in Apoa5 -/- mice, indicating the importance of carboxyl-terminal sequences in Apoa5's function [1,3].

In conclusion, Apoa5 plays a vital role in regulating plasma triglyceride metabolism through its interaction with ANGPTL3/8 and modulation of LPL activity. Studies using Apoa5 -/- mouse models have significantly contributed to understanding its role in hypertriglyceridemia, suggesting potential therapeutic strategies such as using ANGPTL3/8-specific antibodies to mimic Apoa5's function for treating elevated plasma lipid levels [1].

References:

1. Yang, Ye, Konrad, Robert J, Ploug, Michael, Young, Stephen G. 2024. APOA5 deficiency causes hypertriglyceridemia by reducing amounts of lipoprotein lipase in capillaries. In Journal of lipid research, 65, 100578. doi:10.1016/j.jlr.2024.100578. https://pubmed.ncbi.nlm.nih.gov/38880127/

2. Guardiola, Montse, Ribalta, Josep. . Update on APOA5 Genetics: Toward a Better Understanding of Its Physiological Impact. In Current atherosclerosis reports, 19, 30. doi:10.1007/s11883-017-0665-y. https://pubmed.ncbi.nlm.nih.gov/28500476/

3. Chen, Yan Q, Yang, Ye, Zhen, Eugene Y, Young, Stephen G, Konrad, Robert J. 2024. Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity. In Proceedings of the National Academy of Sciences of the United States of America, 121, e2322332121. doi:10.1073/pnas.2322332121. https://pubmed.ncbi.nlm.nih.gov/38625948/

4. Talmud, Philippa J. 2007. Rare APOA5 mutations--clinical consequences, metabolic and functional effects: an ENID review. In Atherosclerosis, 194, 287-92. doi:. https://pubmed.ncbi.nlm.nih.gov/17222847/

5. Chen, Yan Q, Pottanat, Thomas G, Zhen, Eugene Y, Qian, Yue-Wei, Konrad, Robert J. 2021. ApoA5 lowers triglyceride levels via suppression of ANGPTL3/8-mediated LPL inhibition. In Journal of lipid research, 62, 100068. doi:10.1016/j.jlr.2021.100068. https://pubmed.ncbi.nlm.nih.gov/33762177/