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ANGPTL3

Official Full Name
angiopoietin like 3
Organism
Homo sapiens
GeneID
27329
Background
This gene encodes a member of a family of secreted proteins that function in angiogenesis. The encoded protein, which is expressed predominantly in the liver, is further processed into an N-terminal coiled-coil domain-containing chain and a C-terminal fibrinogen chain. The N-terminal chain is important for lipid metabolism, while the C-terminal chain may be involved in angiogenesis. Mutations in this gene cause familial hypobetalipoproteinemia type 2. [provided by RefSeq, Aug 2015]
Synonyms
ANL3; ANG-5; FHBL2; ANGPT5;
Bio Chemical Class
Fibrinogen protein
Protein Sequence
MFTIKLLLFIVPLVISSRIDQDNSSFDSLSPEPKSRFAMLDDVKILANGLLQLGHGLKDFVHKTKGQINDIFQKLNIFDQSFYDLSLQTSEIKEEEKELRRTTYKLQVKNEEVKNMSLELNSKLESLLEEKILLQQKVKYLEEQLTNLIQNQPETPEHPEVTSLKTFVEKQDNSIKDLLQTVEDQYKQLNQQHSQIKEIENQLRRTSIQEPTEISLSSKPRAPRTTPFLQLNEIRNVKHDGIPAECTTIYNRGEHTSGMYAIRPSNSQVFHVYCDVISGSPWTLIQHRIDGSQNFNETWENYKYGFGRLDGEFWLGLEKIYSIVKQSNYVLRIELEDWKDNKHYIEYSFYLGNHETNYTLHLVAITGNVPNAIPENKDLVFSTWDHKAKGHFNCPEGYSGGWWWHDECGENNLNGKYNKPRAKSKPERRRGLSWKSQNGRLYSIKSTKMLIHPTDSESFE
Open
Disease
Blood/blood-forming organ sympton, Cardiovascular disease, Hyper-lipoproteinaemia, Knee osteoarthritis
Approved Drug
1 +
Clinical Trial Drug
5 +
Discontinued Drug
0

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Detailed Information

Emerging as a crucial actor in lipid metabolism and a potential target for cardiovascular disease therapy is angiopoietin-like 3 (ANGPTL3). Mostly found in the liver, this secreted protein falls into the angiopoietin-like protein family, which also contains ANGPTL4 and ANGPTL8. ANGPTL3 has attracted a lot of interest as research keeps revealing the complicated interactions between lipid metabolism and cardiovascular health for its many functions and therapeutic possibilities.

Structure and Expression of ANGPTL3

The ANGPTL3 gene generates a protein that is further processed into two different chains, thereby encoding ANGPTL3. Whereas the C-terminal chain has a fibrinogen-like domain (FLD), which is essential for ligand action, the N-terminal chain has a coiled-coil domain (CCD) that enables homooligomer formation. Between these domains is a linker region; before the CCD, a very hydrophobic signal peptide sequence common of released proteins.

ANGPTL3 expresses itself mostly in hepatocytes in the liver. Many elements influence its regulation; the liver X receptor (LXR) is especially important. Potential ANGPTL3 mRNA inhibitors are PPARδ, statins, insulin, leptin, thyroid hormones, and lipopolysaccharides among other factors. This complex control emphasizes the need for the protein to maintain metabolic equilibrium.

Biological Functions of ANGPTL3

ANGPTL3's most notable role is in its capacity to control lipid metabolism. It mostly works by blocking lipoprotein lipase (LPL), a crucial enzyme that breaks down very low-density lipoproteins (VLDL) into free fatty acids and glycerol and forms triglycerides in chylomicrons. ANGPTL3 raises plasma triglyceride levels by thus reducing LPL activity.

LPL inhibition by ANGPTL3 is mediated by a complex process including the recruitment of proprotein convertases PCSK6 and FURIN to LPL. This results in LPL from cell surface cleaving and separation under the N-terminal domain of ANGPTL3 mediation. Fascinatingly, its activity is neither hampered by GPIHBP1, a protein usually stabilizing and activating LPL, nor by proteolytic cleavage of ANGPTL3 itself.

Apart from its effects on LPL, ANGPTL3 also reduces endothelial lipase (EL). Reduced plasma levels of phospholipids and high-density lipoprotein (HDL) cholesterol follow from this inhibition. ANGPTL3's simultaneous inhibition of LPL and EL helps to explain its wide influence on lipid profiles, thereby influencing levels of LDL-C, VLDL-C, HDL-C, and triglycerides:

Angiogenesis and Cell Signaling

Although ANGPTL3 plays most of a function in lipid metabolism, it also influences angiogenesis and cell signaling mechanisms. Via integrin alpha-V/beta-3 (ITGAV: ITGB3), it hooks endothelial cells to activate MAPK, FAK, and Akt signaling pathways. This association enhances cell adhesion and migration, therefore supporting the angiogenic characteristics of the protein.

ANGPTL3 released from podocytes may alter the glomerular endothelial cell characteristics in the kidneys using integrin alpha-V/beta-3 and Akt signaling. Implicating integrin alpha-V/beta-3 and Rac1 activation, may also boost podocyte motility and cause actin filament rearranging in these cells.

New data point to ANGPTL3's involvement in hematopoietic stem cell (HSC) activity control. The protein hooks to HSCs and could be involved in the down-regulation of IKZF1/IKAROS, hence altering their activity. This ability emphasizes the many physiological effects of ANGPTL3 outside of lipid metabolism.

Disease and Therapeutic Potential

Mutations in the ANGPTL3 gene cause familial hypobetalipoproteinemia type 2, characterized by low levels of apolipoprotein B-containing lipoprotein. This genetic link stresses the importance of ANGPTL3 in lipid control and provides potential therapies for lipid-related illnesses.

ANGPTL3 and cardiovascular disease risk have been widely researched. ANGPTL3 loss-of-function mutations are associated with lower LDL-C levels and an increased risk of cardiovascular events. A thorough genetic examination of more than 90,000 people discovered that these mutations were associated with lower LDL-C levels and a reduced risk of cardiovascular disease than the general population.

Figure 1 outlines the pharmacological targets of current or potential lipid-lowering agents for dyslipidemia therapy, highlighting strategies for inhibiting these targets in lipid and lipoprotein metabolism.Figure 1. Pharmacological targets for existing or potential lipid-lowering agents in dyslipidemia therapy. (Chen PY et al., 2021)

Other proof of ANGPTL3's impact on cardiovascular health comes from clinical studies. Myocardial infarction risk was 29% lower in individuals with lowest plasma ANGPTL3 levels than in those in the top three quartiles of ANGPTL3 concentrations. These results imply that aiming at ANGPTL3 might be a good approach to lower the cardiovascular disease risk.

References:

  1. Chen PY, Gao WY, Liou JW, et al. Angiopoietin-Like Protein 3 (ANGPTL3) Modulates Lipoprotein Metabolism and Dyslipidemia. Int J Mol Sci. 2021;22(14):7310.
  2. Kersten S. ANGPTL3 as therapeutic target. Curr Opin Lipidol. 2021;32(6):335-341.
  3. Tikka A, Jauhiainen M. The role of ANGPTL3 in controlling lipoprotein metabolism. Endocrine. 2016;52(2):187-193.
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