The Effect of PCSK9 Loss-of-Function Variants on the Postprandial Lipid and ApoB-Lipoprotein Response

Abstract

Participants carrying PCSK9-LOF variants had attenuated levels of fasting and postprandial TG, apoB48, and total apoB. This may confer protection from CVD and further validate the use of PCSK9 inhibitors to lower CVD risk.

Efficacy and safety of proprotein convertase subtilisin/kexin 9 inhibitors in people with diabetes and dyslipidaemia

“…An alternative explanation is that PCSK9 affects the clearance of TRLs via the LDLR pathway, which is supported by the inverse association of plasma PCSK9 levels with the fractional clearance of APOB48‐containing lipoproteins observed in a post‐prandial kinetic study in obese subjects . Subjects with PCSK9 loss‐of‐function variants and mice lacking Pcsk9 are also protected against post‐prandial hyperlipidaemia, an effect that appears to be predominantly explained by an increased hepatic clearance of chylomicron remnants via a LDLR‐mediated re‐uptake . Taking into account the increased plasma PCSK9 levels in T2DM patients and the positive relationship between plasma PCSK9 and plasma TG levels, it seems thus important to address two specific questions: (a) is the efficacy of PCSK9 inhibitors to lower plasma LDL‐C levels different between non‐diabetic and T2DM patients, and (b) can PCSK9 inhibitors effectively modulate the levels of TRLs in T2DM patients?…”

“…Specifically, plasma PCSK9 levels associate with (large) VLDLs, VLDL remnants and intermediate‐density lipoproteins (IDLs) in subjects with T2DM and/or metabolic syndrome . Genetic studies have also demonstrated that specific gain‐of‐function variants (notably p.S127R and p.D374Y) modestly increase plasma TG levels, whereas certain loss‐of‐function variants (p.Y142X, p.C679X, p.R46L) modestly lower plasma TG levels . One potential explanation for the positive relationship between plasma TG and plasma PCSK9 levels is an intracellular effect of PCSK9 on APOB/VLDL secretion.…”

“…44 Genetic studies have also demonstrated that specific gain-of-function variants (notably p.S127R and p.D374Y) modestly increase plasma TG levels, 45,46 whereas certain loss-of-function variants (p.Y142X, p.C679X, p.R46L) modestly lower plasma TG levels. 17,47,48 One potential explanation for the positive relationship between plasma TG and plasma PCSK9 levels is an intracellular effect of PCSK9 on APOB/VLDL secretion. Indeed, the over-expression of wild-type PCSK9 or the p.S127R and p.D374Y gain-of-function variants promoted the secretion of APOB from hepatocytes.…”

PCSK9 Inhibitors in Lipid Management of Patients With Diabetes Mellitus and High Cardiovascular Risk: A Review

“…Whereas the LDLR binds to LDLs via apolipoprotein‐B100 (apoB100),36 LDLR binds triglyceride‐rich lipoprotein remnants through interactions with apolipoprotein‐E (apoE), and clearance of these particles occurs along with other receptors such as LDLR‐related protein 1 and Syndecan‐1 37, 38. The recent study showed lower levels of fasting and postprandial triglycerides, apoB48 (an indicator of remnant lipoprotein metabolism), and total apoB (a surrogate of apoB100) in individuals carrying loss‐of‐function PCSK9 genetic variants, supporting a role of PCSK9 in the reduction of uptake of apoE‐containing remnant particles as well as LDL 31. Recent kinetic studies in healthy subjects showed that PCSK9 inhibitors decreased fractional production rate of LDL and intermediate‐density lipoprotein, and increased fractional clearance rates of very‐low‐density lipoprotein, intermediate‐density lipoprotein, and LDL particles, which may reflect a much higher expression of hepatic LDLRs than with statin treatment 39, 40.…”

“…In addition to the well‐established role of PCSK9 in LDL metabolism, a recent study suggested that it could play a significant role in the metabolism of triglyceride‐rich lipoproteins also through interaction with the LDLR 31. This has important implications for individuals with type 2 diabetes mellitus (T2D), and for those with type 1 diabetes mellitus (T1D) with poor glycemic control, who typically have a pattern of lipid abnormalities related to insulin resistance that is characterized by reduced hepatic clearance of triglyceride‐rich lipoproteins, increased hepatic production of very‐low‐density lipoproteins, and enhanced intestinal production of chylomicrons 32.…”