Last Updated: May 23, 2024
Introduction to Angiopoietin-Like Protein 3: ANGPTL3
Angiopoietin-like protein 3 (also known as angiopoietin 5) is produced exclusively by the liver and secreted into the circulation. Prior to its release from hepatocytes, a portion of the angiopoietin-like protein 3 proprotein is cleaved into N-terminal and C-terminal fragments via the action of proprotein convertase subtilisin/kexin type (PCSK) family member enzyme, furin (encoded by the FURIN gene). Furin is also known as PCSK3.
Both the full-length and the cleaved fragments of angiopoietin-like protein 3 proprotein are secreted into the circulation. The N-terminal portion of angiopoietin-like protein 3 is involved in the regulation of overall lipoprotein metabolism through its ability to inhibit the activity of lipoprotein lipase (LPL), as well as to inhibit the activity of endothelial lipase, EL. Endothelial lipase is so-called because it is expressed exclusively by endothelial cells. Endothelial lipase functions almost exclusively as a phospholipase with highest affinity for HDL. The C-terminal fragment of angiopoietin-like protein 3 is involved in angiogenesis.
Molecular Biology of ANGPTL3
Angiopoietin-like protein 3 is encoded by the ANGPTL3 gene. The ANGPTL3 gene is located on chromosome 1p31.3 and is composed of 7 exons that encode a 460 amino acid preproprotein. Mutations in the ANGPTL3 gene that cause familial combined hypolipidemia have only recently (2010) been described. The most commonly detected ANGPTL3 mutation is a double nonsense mutation affecting codon 17 such that the normal Ser (S) codon at that position (TCC) is mutated to a stop codon, TGA. This mutation is referred to as the S17X mutation. Another nonsense mutation in the ANGPTL3 gene at codon 129 changes the normal Glu (E) codon (GAA) to a stop codon, TAA. This mutation if referred to as the E129X mutation.
The ANGPTL3 mutations are associated with reduced levels of both apolipoprotein B-100 (apoB-100; >48% reduction) containing lipoproteins (VLDL and LDL) as well as reduced levels of apoA-I containing lipoproteins (HDL; >46% reduction), hence the designation of familial combined hypolipoproteinemia. In addition to reduced VLDL/LDL and HDL patients experience reduced serum triglycerides.
Clinical Features of ANGPTL3 Deficiency
Familial combined hypolipidemia refers to a dyslipidemia that is the result of the inheritance of homozygous mutations in the gene (ANGPTL3) encoding angiopoietin-like protein 3. Familial combined hypolipidemia has also been called familial hypobetalipoproteinemia type 2. Because of the associated hypobetalipoproteinemia, familial combined hypolipidemia actually belongs to the family of hypolipidemic disorders identified as familial hypobetalipoproteinemia syndrome, FHBL. The characteristics of the most common cause of FHBL result from mutation in the APOB gene.
In addition to mutations in the APOB gene that lead to truncation of the apolipoprotein B-100 protein, loss-of-function mutations in the gene (PCSK9) encoding proprotein convertase subtilisin/kexin type 9 are also associated with disorders that can be included in the spectrum of FHBL. In contrast to the risk for hepatic steatosis with APOB and PCSK9 mutations causing FHBL, the ANGPTL3 mutations are not found to be associated with hepatic steatosis or other associated hepatic pathologies.
Heterozygotes for loss-of-function mutations in the ANGPTL3 gene (S17X and E129X) experience intermediate levels of LDL-cholesterol and triglycerides. On the other hand, compound heterozygotes show a marked reduction in HDL-cholesterol in addition to a reduction in LDL-cholesterol and triglyceride.
Individuals homozygous for the S17X mutation have on average a 48% reduction in LDL, a 62% reduction in triglyceride, a 46% reduction in HDL, a 44% reduction in apoB, and a 48% reduction in apoA-I. On the other hand S17X heterozygotes show reductions in total cholesterol and HDL but not have reduced levels of LDL or triglyceride.
Homozygous or compound heterozygotes other loss-of-function frame-shift mutations in exon 1 showed no ANGPTL3 in the blood and marked reductions of triglyceride-containing lipoproteins and HDL particles that contained only apoA-I. In these latter individuals reverse cholesterol efflux via the ABCA1, ABCG1, and SR-BI pathways was reduced leading to the plasma HDL-cholesterol levels seen in these patients. However, despite the reduced HDL levels there was no clinical evidence for atherosclerosis. Heterozygotes for these same loss-of-function frame-shift mutations have reduced LDL levels but normal HDL levels.
The prevalence of ANGPTL3 mutations causing combined hypolipidemia in patients with primary hypobetalipoproteinemia (FHBL) is around 10% of total cases. In these patients, where HDL levels were below the second decile, no mutations in the apoB gene were found. However, when HDL levels were above the second decile, the prevalence of apoB mutations was on the order of 8%. The clinical significance of these findings suggests that when HDL levels are low in FHBL, mutations in the ANGPTL3 gene are more likely whereas when HDL levels are normal, mutations in the apoB gene are more likely.