Circulating PCSK9 levels and CETP plasma activity are independently associated in patients with metabolic diseases

Girona J, Ibarretxe D, Plana N, et al.
Cardiovasc Diabetol 2016;15:107

Background

Proprotein convertase subtilisin/kexin 9 (PCSK9) mediates LDL receptor (LDLR) degradation in lysosomes and decreases the LDL-C clearance from the circulation, thereby increasing LDL-C plasma levels [1]. PCSK9 inhibitors reduce LDL-C levels by more than 60 % [2].
Cholesteryl ester transfer protein (CETP) mediates the transport of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins such as VLDL and LDL. There are data supporting that the inhibition of CETP may lead to increased HDL-C levels and reduced LDL-C levels [3-6].
Since both PCSK9 and CETP genes are regulated by the SREBP transcription factor family, there might be a metabolic relationship between these molecules [7,8]. This hypothesis is supported by recent data according to which CETP inhibitors influence PCSK9 levels as an off-target effect [9-11].
The current study examined the relationship between plasma CETP activity and PCSK9 levels in 450 patients with metabolic disturbances, who were not on lipid-lowering therapy. The impact of the loss-of-function (LOF) PCSK9 genetic variant rs11591147 (R46L) was studied as well.

Main results

• There was a significant positive association between PCSK9 and CETP (r=0.256; P<0.001), which remained significant after adjustment for age, gender, BMI, SBP, LDL-C, triglycerides and glucose (r=0.158; P=0.003).

• CETP activity showed a positive association with LDL particle number (r=0.300, P<0.001) and with small and large HDL particles (r=0.241, P<0.001 and r=0.109, P=0.021, respectively), but a negative association with medium HDL particles (r = −0.193; P < 0.001).

• PCSK9 showed positive associations with LDL (r=0.179, P<0.0001) and LDL particle number (r=0.134, P=0.004), and an inverse relation with LDL size (r=-0.107, P=0.023).
• In a linear regression model, the relation between CETP activity and PCSK9 remained robust after additional adjustment for age, gender, BMI, SBP, LDL-C, triglycerides, glucose, LCAT and metabolic syndrome (beta 0.110; P = 0.003, R²=0.624).

• Individuals with the PCSK9 R46L LOF mutation (seen in 5.2%) not only had significant lower levels of LDL-C (2.55 (2.40–3.46) mmol/L vs 3.28 (2.55–4.08); P = 0.010) and PCSK9 (193.6 (147.8– 264.9) vs 328.8 (258.9–410.2) ng/mL; P < 0.0001), but also CETP activity was lower than in non-R46L mutation-carriers: 10.15 (9.59–11.93) vs 11.65 (10.31–13.50) nmol/L per h; P = 0.009.

Conclusion

In 450 patients with metabolic disturbances putting them at increased CV risk, who were not on lipid-lowering therapy, PCSK9 plasma concentration was moderately but directly correlated with CETP activity, independently of multiple confounding covariates. While the mechanism underlying the association is not yet known, CETP and PCSK9 share molecular regulatory mechanisms, and these findings may be relevant to explain the broad lipid effects of PCKS9 and CETP inhibition.

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