Abstract 197: Characterization of the Effects of Angiopoietin-Like 3 on Plasma Lipids and Lipoproteins in Humans

Abstract

Angiopoietin-like 3 (ANGPTL3) deficiency due to loss-of-function (LOF) gene mutations causes familial combined hypobetalipoproteinemia type 2 (FHBL2) in homozygotes and compound heterozygotes, with a lipid phenotype much milder in heterozygotes. We aim to determine whether a critical reduction in plasma ANGPTL3 levels is a major determinant of FHBL2 lipid phenotype. We studied 126 subjects from 19 families with ANGPTL3 LOF mutations. Individuals homozygous for mutations in ANGPTL3 manifest the full FHBL2 phenotype of reduced total cholesterol, triglycerides, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol (-C) and particle concentration (-p), and LDL size. Heterozygotes only displayed with low total cholesterol, HDL-C, HDL-p and VLDL-p compared with non-carriers. Using multivariate adaptive regression splines, we found that: ( i ) total cholesterol, triglycerides, LDL-C, HDL-C, HDL-p, and LDL size correlated with ANGPTL3 but only for levels below 25% of normal (<60 ng/dl); ( ii ) VLDL-p and LDL-p correlate with ANGPTL3 irrespective of its plasma levels; and ( iii ) homozygotes exhibited reduced levels of mature proprotein convertase subtilisin/kexin type 9 (PCSK9), a known regulator of plasma LDL-C levels. These results indicate that the full FHBL2 phenotype seen in homozygous carriers of LOF mutations in ANGPTL3 is caused by a critical reduction of more than 75% of its plasma levels, thus uncovering the relationship between mutation status, plasma ANGPTL3 concentrations, and the lipid phenotype. Furthermore, our study suggests that the low plasma LDL seen in homozygous carriers of ANGPTL3 LOF mutations is mediated by the modulation of plasma PCSK9.