ANGPTL3 (Angiopoietin-Like Protein 3 Lipase Inhibitor Gene)
ANGPTL3 (angiopoietin like 3; HGNC:491, NCBI Gene ID 27329) is a human locus mapped to chromosome band 1p31.3 that encodes secreted hepatokine Angiopoietin-like protein 3 (460 aa). ANGPTL3 acts in intravascular inhibition of lipoprotein lipase (LPL) & endothelial lipase (LIPG), together with ANGPTL4 (Fasting Lipase Inhibitor Gene), ANGPTL8 (Betatrophin / Feeding Co-Factor Gene), and LPL (Lipoprotein Lipase Gene). Encodes the liver-secreted hepatokine ANGPTL3 that inhibits lipoprotein lipase and endothelial lipase.
Approved Symbol
ANGPTL3
Chromosomal Locus
1p31.3
Encoded Product
Secreted hepatokine Angiopoietin-like protein 3 (460 aa)
Primary Pathway
Intravascular inhibition of lipoprotein lipase (LPL) & endothelial lipase (LIPG)
Clinical / Therapeutic Role
LoF causes familial combined hypolipidemia; target of evinacumab, zodasiran siRNA & VERVE-201 base editing
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 7-exon gene nested inside intron 16 of the DOCK7 locus on chromosome 1p31.3, encoding a 460-amino-acid secreted glycoprotein containing an N-terminal coiled-coil lipase-inhibitory domain, a furin cleavage linker (Arg221-Arg224), and a C-terminal fibrinogen-like domain.
Cellular & Tissue Expression Profile: Expressed and secreted almost exclusively by hepatic hepatocytes under transcriptional activation by liver X receptors (LXR) and HNF1alpha, operating independently of fasting or feeding state unless complexed with ANGPTL8.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Catalyzes the unfolding and irreversible inactivation of intravascular lipoprotein lipase (LPL, especially when complexed with ANGPTL8 after feeding) and endothelial lipase (LIPG), thereby elevating circulating triglycerides, VLDL remnants, HDL-cholesterol, and LDL-cholesterol via an LDLR-independent pathway.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Biallelic loss-of-function mutations (such as p.Ser17Ter in the Campodimele Italian kindred) cause familial combined hypolipidemia (FHBL2), characterized by lifelong 60–70% reductions in plasma triglycerides, LDL-cholesterol, and HDL-cholesterol, enhanced insulin sensitivity, and near-complete protection from atherosclerotic cardiovascular disease without hepatic steatosis.
Therapeutic & Clinical Pharmacology: Clinically targeted by the FDA-approved monoclonal antibody evinacumab (Evkeeza) for homozygous familial hypercholesterolemia (effective even in LDLR-null patients), GalNAc-conjugated siRNAs (zodasiran, solbinsiran), and in vivo CRISPR adenine base editing (VERVE-201).