ANGPTL3

ANGPTL3 Full Name

angiopoietin-like 3

ANGPTL3 Introduction

ANGPTL3 (angiopoietin‑like protein 3) is a secreted glycoprotein that plays a key role in the regulation of lipid metabolism, particularly in the control of triglyceride and cholesterol levels. The gene encoding ANGPTL3 is located on human chromosome 1p31.3 and produces a protein of approximately 460 amino acids with a molecular weight of about 55–60 kDa. ANGPTL3 is predominantly expressed in the liver and, to a lesser extent, in the kidney and adipose tissue. Unlike angiopoietins, which bind to the Tie2 receptor, ANGPTL3 does not bind Tie receptors but instead inhibits the activity of lipoprotein lipase (LPL) and endothelial lipase (EL), thereby reducing the clearance of triglyceride‑rich lipoproteins and high‑density lipoprotein (HDL) cholesterol. Loss‑of‑function mutations in ANGPTL3 cause familial combined hypolipidemia (FHBL2), a condition characterized by very low levels of low‑density lipoprotein (LDL) cholesterol, HDL cholesterol, and triglycerides. This observation has made ANGPTL3 an attractive therapeutic target for lowering atherogenic lipoproteins.

Figure 1. Strcuture of ANGPTL3.

Mechanism of Action: Inhibition of Lipoprotein Lipase and Endothelial Lipase

The primary function of ANGPTL3 is to inhibit the activity of two key enzymes involved in plasma lipoprotein metabolism: lipoprotein lipase (LPL) and endothelial lipase (EL). LPL is anchored to the luminal surface of capillary endothelium and hydrolyzes triglycerides in chylomicrons and very low‑density lipoproteins (VLDL), releasing free fatty acids for uptake by muscle and adipose tissue. ANGPTL3 binds directly to LPL and converts the active dimeric enzyme into inactive monomers, thereby reducing triglyceride clearance and raising plasma triglyceride levels. The N‑terminal coiled‑coil domain is both necessary and sufficient for this inhibition. ANGPTL3 also inhibits EL, which hydrolyzes HDL phospholipids and contributes to HDL cholesterol clearance. By inhibiting EL, ANGPTL3 reduces HDL catabolism, leading to higher HDL cholesterol levels. The combined effect of ANGPTL3 inhibition is to lower circulating triglycerides, LDL cholesterol, and HDL cholesterol, which explains why ANGPTL3 deficiency results in hypolipidemia. ANGPTL3 is also regulated by nutritional status: it is induced by fasting and suppressed by feeding, and its expression is controlled by liver X receptors (LXRs) and thyroid hormone.

Therapeutic Targeting of ANGPTL3: Evinacumab
The discovery that ANGPTL3 loss‑of‑function protects against atherosclerosis without causing adverse effects has spurred the development of ANGPTL3 inhibitors. Evinacumab is a fully human monoclonal antibody that binds to and neutralizes ANGPTL3. It is administered intravenously and has been approved by the FDA for the treatment of homozygous familial hypercholesterolemia (HoFH) as an adjunct to other lipid‑lowering therapies. Clinical trials have demonstrated that evinacumab reduces LDL cholesterol by approximately 50% in HoFH patients, including those with null LDL receptor mutations who respond poorly to statins and PCSK9 inhibitors. Evinacumab also lowers triglycerides, HDL cholesterol, and apolipoprotein B. The drug is generally well tolerated, with mild injection site reactions and nasopharyngitis being the most common side effects. Other ANGPTL3‑targeting strategies include antisense oligonucleotides (e.g., vupanorsen) and small interfering RNA (siRNA) approaches, though some have been associated with adverse hepatic effects. ANGPTL3 inhibition represents a novel mechanism for lowering atherogenic lipoproteins that is independent of the LDL receptor pathway, making it particularly valuable for patients with refractory hypercholesterolemia.

Alternate Names for ANGPTL3

ANGPTL3; angiopoietin-like 3; ANL3; ANG-5; FHBL2; ANGPT5; angiopoietin-related protein 3; angiopoietin 5;