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. 2010 Feb;51(2):345-51.
doi: 10.1194/jlr.M000620. Epub 2009 Sep 8.

Fenofibrate treatment increases human serum proprotein convertase subtilisin kexin type 9 levels

Jason S Troutt  1 , William E Alborn, Guoqing Cao, Robert J Konrad
Affiliations

Fenofibrate treatment increases human serum proprotein convertase subtilisin kexin type 9 levels

Jason S Troutt et al. J Lipid Res. 2010 Feb.

Abstract

Over the past several years, proprotein convertase subtilisin kexin type 9 (PCSK9) has gained significant attention as a key regulator of serum LDL-cholesterol (LDL-C) levels. In humans, gain-of-function mutations in PCSK9 cause a form of familial hypercholesterolemia, whereas loss-of-function mutations result in significantly decreased LDL-C and cardiovascular risk. Our laboratory was the first to demonstrate that atorvastatin increases PCSK9 serum levels, an observation that has since been confirmed by at least two other groups. In light of these observations, we studied the effect of another common lipid-lowering medication, fenofibrate, on circulating PCSK9 protein levels in patients treated with fenofibrate or placebo for 12 weeks. We observed that fenofibrate (200 mg per day) significantly increased circulating PCSK9 levels by 25% compared with baseline. Placebo treatment, in comparison, had no effect on PCSK9 levels. Interestingly, fenofibrate-induced increases in serum PCSK9 levels were highly correlated with fenofibrate-induced changes in HDL-C and triglyceride levels, as well as with fenofibrate-induced changes in LDL-C levels. These results suggest an explanation for why fibrates do not achieve as much LDL-C lowering as might otherwise be expected and indicate that the addition of a PCSK9 inhibitor to fibrate therapy may result in additional beneficial LDL-C lowering.

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Figures

Fig. 1.
Fig. 1.
Effect of fenofibrate on serum HDL-C and triglyceride levels. A: Baseline and endpoint samples from patients receiving placebo only for 12 weeks or fenofibrate only (200 mg per day) for 12 weeks were analyzed for HDL-C levels. Levels at baseline and endpoint were plotted for each group. Data are expressed as the mean ± SEM. Fenofibrate treatment caused a significant 19% increase in serum HDL-C. B: Patient samples described in Fig. 1A were analyzed for serum triglyceride levels. Data are expressed as the mean ± SEM. Fenofibrate treatment caused a 23% decrease in serum triglycerides, which did not achieve statistical significance.
Fig. 2.
Fig. 2.
Effect of fenofibrate on serum PCSK9 and LDL-C levels. A: Baseline and endpoint samples from patients receiving placebo only for 12 weeks or fenofibrate only (200 mg per day) for 12 weeks were analyzed for PCSK9 levels using a dual monoclonal antibody PCSK9 sandwich ELISA method. Data are expressed as the mean ± SEM. Fenofibrate treatment caused a significant 25% increase in serum PCSK9 levels. B: Patient samples described in Fig. 2A were analyzed for serum LDL-C levels. Data are expressed as the mean ± SEM. Fenofibrate treatment caused a 10% decrease in serum LDL-C, which did not achieve statistical significance.
Fig. 3.
Fig. 3.
PCSK9 immunoprecipitation and Western blotting analysis of patient serum samples. In order to confirm the effect of fenofibrate treatment on serum PCSK9 levels, representative patient serum samples that still had adequate volume remaining were immunoprecipitated with the same anti-PCSK9 capture monoclonal antibody used in the ELISA. Afterward, immunoprecipitates were analyzed via Western blotting with HRP-labeled polyclonal anti-PCSK9 antibody. Both baseline and endpoint samples from representative placebo and fenofibrate treated patients were analyzed. The predominant band indicated with the arrow represents intact PCSK9 protein. The mobility of the band immediately below is consistent with the furin cleavage product of PCSK9 while the mobility of the band at the bottom of the blot is consistent with PCSK9 propeptide (29). Results were compared with those obtained using the PCSK9 ELISA described in Fig. 2A. Results obtained via immunoprecipitation and Western blotting compared well with those obtained by ELISA, confirming the effect of fenofibrate treatment on PCSK9 levels.
Fig. 4.
Fig. 4.
Relationship of fenofibrate-induced percent changes in serum PCSK9 levels compared with percent changes in LDL-C, HDL-C, and triglyceride levels. A: Percentage changes in serum PCSK9 levels from baseline to endpoint in patients receiving fenofibrate (200 mg per day) for 12 weeks were correlated with percentage changes in serum LDL-C levels. Percent changes in PCSK9 levels were negatively significantly correlated with percent changes in LDL-C levels. (r = −0.48, p = 0.03). B: Percentage changes in serum PCSK9 levels from baseline to endpoint in patients receiving fenofibrate (200 mg per day) for 12 weeks were correlated with percentage changes in serum HDL-C levels. Percent changes in PCSK9 levels were negatively significantly correlated with percent changes in HDL-C levels. (r = −0.59, p < 0.01). C: Percentage changes in serum PCSK9 levels from baseline to endpoint in patients receiving fenofibrate (200 mg per day) for 12 weeks were correlated with percentage changes in serum triglyceride levels. Percent changes in PCSK9 levels were positively significantly correlated with percent changes in triglyceride levels. (r = 0.60, p < 0.01).
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