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Several proprotein convertase subtilisin/kexin (PCSK) members are involved in high-density lipoprotein (HDL) metabolism. We investigated the potential role of PCSK1 in HDL metabolism.
A mouse model (PCSK1N222D) containing an amino acid substitution (N->D) at position 222 in PCSK1 was used to test whether HDL metabolism is affected.
HDL cholesterol concentration and apolipoprotein A1 (APOA1) serum levels were compared between wild-type (PCSK1WT) and PCSK1N222D. HDL cholesterol concentration was not affected, but the APOA1 level was increased in the non-HDL fraction of PCSK1N222D, indicating that the unbound APOA1 is increased. We hypothesized that some of the secreted APOA1 remains in the lipid-free form due to inefficient APOA1-lipidation mediated by two enzymes: phospholipid transfer protein (PLTP) and lecithin-cholesterol acyltransferase (LCAT). PLTP activity was lower in PCSK1N222D serum when APOA1 and HDL cholesterol concentrations were induced by a diet supplemented with vitamin D, suggesting that lower PLTP activity in PCSK1N222D serum is a cause of lipid-free APOA1 induction.
Our data suggests a role for PCSK1 in HDL metabolism and an interaction with PLTP.