The exact mechanism by which ANGPTL3 deficiency lowers LDL and VLDL-TG is not completely understood. To get more insight into these mechanisms, we planned to measure in vivo turnover of TG- and apoB-containing lipoproteins (VLDL and LDL) in subjects with complete and partial ANGPTL3 deficiency (caused by homozygous or heterozygous LoF mutations in ANGPTL3 gene) in comparison with healthy controls. To this aim, 30 subjects will receive infusion of d3-leucine to assess the kinetics of apoB-containing lipoproteins and a bolus injection of d5-glycerol to assess the kinetics of triglycerides associated with different lipoprotein fractions.
As the deficiency of ANGPTL3 is a rare condition, we have planned to include in this study 10 individuals already identified by Dr. Stitziel at Washington University at St. Louis (USA). We estimated that this sample size will give an 80% power to detect a significant difference in lipoprotein turnover.
As we have recently observed an association between ANGPTL3 deficiency and lower plasma levels of PCSK9 (a major player in the regulation of LDLR activity), we will also investigate in two hepatoma cell lines, Huh7 and HepG2, the effect of ANGPTL3 silencing on expression and activity of PCSK9 and LDLR.
Our overall hypothesis is that 1) ANGPTL3-deficient subjects have a decreased production rate of VLDL and LDL associated with a decreased TG synthesis and increased catabolism of LDL than control and 2) ANGPTL3-deficient cells show a decreased transport and secretion of PCSK9 and this is associated with increased expression of LDLR at the cell surface.
If these hypotheses will be confirmed, our results, not only, will further support the importance to develop new anti-ANGPTL3 therapeutic strategies but also will provide potential indications for these compounds into the different hyperlipemic phenotypes.
