Angiopoietin-Like Protein 3 (ANGPTL3) Modulates Lipoprotein Metabolism and Dyslipidemia

Abstract

Dyslipidemia is characterized by increasing plasma levels of low-density lipoprotein-cholesterol (LDL-C), triglycerides (TGs) and TG-rich lipoproteins (TGRLs) and is a major risk factor for the development of atherosclerotic cardiovascular disorders (ASCVDs). It is important to understand the metabolic mechanisms underlying dyslipidemia to develop effective strategies against ASCVDs. Angiopoietin-like 3 (ANGPTL3), a member of the angiopoietin-like protein family exclusively synthesized in the liver, has been demonstrated to be a critical regulator of lipoprotein metabolism to inhibit lipoprotein lipase (LPL) activity. Genetic, biochemical, and clinical studies in animals and humans have shown that loss of function, inactivation, or downregulated expression of ANGPTL3 is associated with an obvious reduction in plasma levels of TGs, LDL-C, and high-density lipoprotein-cholesterol (HDL-C), atherosclerotic lesions, and the risk of cardiovascular events. Therefore, ANGPTL3 is considered an alternative target for lipid-lowering therapy. Emerging studies have focused on ANGPTL3 inhibition via antisense oligonucleotides (ASOs) and monoclonal antibody-based therapies, which have been carried out in mouse or monkey models and in human clinical studies for the management of dyslipidemia and ASCVDs. This review will summarize the current literature on the important role of ANGPTL3 in controlling lipoprotein metabolism and dyslipidemia, with an emphasis on anti-ANGPTL3 therapies as a potential strategy for the treatment of dyslipidemia and ASCVDs.

Keywords: ANGPTL3; ASCVDs; TG-rich lipoproteins; dyslipidemia; lipoprotein lipase.

Figure 1

The pharmacological targets of current or potential lipid-lowering agents for dyslipidemia therapy. ACL, ATP-citrate lyase; ANGPTL3, angiopoietin-like protein 3, Apo(a), Apolipoprotein(a); ApoC-III, Apolipoprotein C-III; ASO, antisense oligonucleotides; CM, chylomicrons; HDL, high-density lipoproteins; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; HMGCR, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase; IDL, intermediate-density lipoprotein; LDL, low-density lipoproteins; LDLR, low-density lipoprotein receptor; LPL, lipoprotein lipase; Lp(a), lipoprotein (a); NPC1L1, Niemann-Pick C1-like 1 protein; PCSK9, proprotein convertase subtilisin/kexin type 9; VLDL, very-low-density lipoproteins. The approaches for inhibition of targets in lipid/lipoprotein metabolism are highlighted in the boxes (created with BioRender.com, accessed on 2 July 2021).

Figure 2

The structural features of ANGPTL3 protein. ANGPTL3 is composed of a signal peptide (SP), an N-terminal coiled-coil domain (CCD) involved in a specific epitope 1 (SE1) for LPL binding and inhibition, a linker region (LR), and a C-terminal fibrinogen-like domain (FLD) with angiogenic properties. The amino acid residues ²²¹RAPR²²⁴↓TT²²⁶ within the LR could be cleaved by furin to yield a N-terminal CCD and a C-terminal FLD in hepatic cells (created with BioRender.com, accessed on 2 July 2021).

Figure 3

Overview of the role of ANGPTL3 in LPL inhibition and TGRL metabolism. Dietary lipid is transported via the blood as part of TG-rich lipoproteins (TGRLs) such as chylomicrons and VLDL, and the TGs are hydrolyzed by lipoprotein lipase (LPL). LPL is synthesized by myocytes or adipocytes and transferred to the cell surface by heparan sulfate proteoglycans (HSPGs). LPL is further transported to the glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) upon the capillary endothelium. ANGPTL3 and ANGPTL8 proteins are produced and secreted by the liver. The ANGPTL3 protein alone or forming a functional complex with ANGPTL8 could markedly inhibit LPL activity (created with BioRender.com, accessed on 2 July 2021).

Figure 4

Strategies for pharmacological inactivation of ANGPTL3. Various strategies have been developed to pharmacologically inactivate ANGPTL3, which include blocking monoclonal antibodies (such as Evinacumab), antisense oligonucleotides (such as Vupanorsen), and a CRISPR genome editing system (such as base editor 3, BE3) for treatment of dyslipidemia. The development of oral, small-molecule inhibitors may serve as a novel pharmacological approach for ANGPTL3 inactivation (created with BioRender.com, accessed on 2 July 2021).