Angiopoietin-related protein 3 (Angptl3) is a member of the angiopoietin-like protein (ANGPTL) family, also known as Ang-5 Angpt5 is involved in the regulation of lipid and glucose metabolism . It is a key regulator of lipoprotein metabolism and can inhibit lipoprotein lipase (LPL) activity. Angptl3 plays an important role in biological processes such as lipid metabolism, angiogenesis, and hematopoiesis, as well as in pathological changes such as atherosclerosis, tumors, nephrotic syndrome, diabetes, and liver disease. It serves as a biomarker for the treatment of these diseases.
Expression distribution of Angptl3
Angptl3 is mainly expressed in hepatocytes and proximal tubule cells, and its expression in the liver is closely related to lipid metabolism.
(Data source: Uniprot)
Structure of Angptl3
Angptl3 is a 70 kDa glycoprotein expressed and secreted by hepatocytes. Its protein structure consists of a 460-amino acid polypeptide with angiopoietin characteristics, including a 16-amino acid signal peptide, an N-terminal coiled-coil domain (CCD), a linker region (LR), and a C-terminal fibrinogen-like domain (FLD) with angiogenic properties. Within the linker region, amino acid residues 221
RAPR 224 ↓TT 226 of Angptl3 are cleaved by the proprotein convertase furin (also known as PCSK3) in hepatocytes, forming the N-terminal coiled-coil domain and the C-terminal fibrinogen-like domain. This is formed by extracellular cleavage by the protein PACE4 (also known as PCSK6). Both the full-length Angptl3 protein and the N-terminally truncated form circulate in plasma. Truncated Angptl3 has enhanced inhibitory effects on EL.
(Data source: Alphafold)
(Data source Chen PY, et al. Int J Mol Sci. 2021)
The role of Angptl3 in lipoprotein metabolism
Angptl3 is a key regulator of lipid metabolism. It directly affects the metabolism of triglycerides (TG) and cholesterol by inhibiting the activity of lipoprotein lipase (LPL) and endothelial lipase (EL).
(1) Angptl3 can promote the secretion of very low-density lipoprotein (VLDL), and its inhibition can correspondingly reduce the secretion of VLDL;
(2) Angptl3 inhibits the activity of lipoprotein lipase (LPL), thereby regulating the clearance rate of triglycerides (TG) in blood vessels and increasing TG levels. Conversely, inhibiting Angptl3 can reduce serum TG levels;
(3) Angptl3 is also involved in the control of the production and clearance of low-density lipoprotein cholesterol (LDL-C). When Angptl3 is inhibited , the level of LDL-C in plasma decreases. This may be because the inhibition of Angptl3 can promote the clearance of VLDL or reduce the secretion of VLDL, thereby further reducing the conversion of VLDL to LDL.
(4) Angptl3 inhibits endothelial lipase (EL), which plays an important role in the catabolism of high-density lipoprotein cholesterol (HDL-C) and very low-density lipoprotein cholesterol (VLDL-C). When Angptl3 is inhibited , the activity of EL can be effectively enhanced, thereby leading to a decrease in HDL-C and VLDL-C levels.
(Data source: Burks KH, et al. Best Pract Res Clin Endocrinol Metab. 2023)
Targeted therapy of Angptl3
Angptl3 on lipid metabolism have aroused great interest in Angptl3 as a molecular target for the prevention or treatment of dyslipidemia and atherosclerotic cardiovascular diseases (ASCVDs). Three strategies for inactivating Angptl3 have been proposed , namely antisense oligonucleotides (ASOs), monoclonal antibodies (evinacumab), and CRISPR-Cas9 genome editing technology.
(Data source: Chen PY, et al. Int J Mol Sci. 2021)
Evinacumab (evinacumab-dgnb, EVKEEZA™), a recombinant human monoclonal antibody, is an angiopoietin-like protein 3 ( Angptl3 ) inhibitor being developed by Regeneron Pharmaceuticals for the treatment of homozygous familial hypercholesterolemia (HoFH), refractory hypercholesterolemia (familial and non-familial), and severe hypertriglyceridemia. Based on results from the Phase 3 ELIPSE HoFH trial, evinacumab is approved in the US as an adjunct to other LDL-C-lowering therapies for the treatment of adults and children aged 12 years and older with HoFH.
