Serum proprotein convertase subtilisin/kexin type 9 concentration is not increased by plant stanol ester consumption in normo- to moderately hypercholesterolaemic non-obese subjects. The BLOOD FLOW intervention study

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low-density lipoprotein (LDL) cholesterol (LDL-C) metabolism by targeting LDL receptors for degradation. Statins increase serum PCSK9 concentration limiting the potential of statins to reduce LDL-C, whereas ezetimibe, inhibitor of cholesterol absorption, has ambiguous effects on circulating PCSK9 levels. Plant stanols also reduce cholesterol absorption, but their effect on serum PCSK9 concentration is not known. Therefore, we performed a controlled, randomized, double-blind study, in which 92 normo- to moderately hypercholesterolaemic subjects (35 males and 57 females) consumed vegetable-oil spread 20 g/day enriched (plant stanol group, n=46) or not (control group, n=46) with plant stanols 3 g/day as ester for 6 months. Fasting blood samples were drawn at baseline and at the end of the study. Serum PCSK9 concentration was analysed with Quantikine Elisa Immunoassay, serum and lipoprotein lipids enzymatically and serum non-cholesterol sterols with GLC. At baseline, PCSK9 concentration varied from 91 to 716 ng/ml with a mean value of 278±11 (S.E.M.) ng/ml with no gender difference. It correlated with serum and LDL-C, serum triglycerides, age, body mass index (BMI) and plasma glucose concentration, but not with variables of cholesterol metabolism when adjusted to serum cholesterol. Plant stanols reduced LDL-C by 10% from controls (P<0.05), but PCSK9 levels were unchanged and did not differ between the groups. In conclusion, the present study demonstrated for the first time that inhibition of cholesterol absorption with plant stanol esters did not affect serum PCSK9 concentration. Thus, plant stanol esters provide an efficient dietary means to lower LDL-C without interfering with the PCSK9 metabolism and in this regard the LDL receptor-mediated cellular cholesterol uptake and removal.

Sex-specific predictors of PCSK9 levels in a European population: The IMPROVE study

“…Regardless of the absolute plasma concentrations of PCSK9, our findings are in line with most previous reports showing that PCSK9 varies with sex, with the exception of two studies that find no gender difference in small cohorts [22,23]. Indeed, we found that PCSK9 plasma concentration was higher in women than in men, in both the univariate and the multivariable analysis, and this result is in agreement with studies in large, ethnically diverse, general populations [7,18,24], in a large population-based sample of children and adolescents [25], and in diverse cohorts of patients with stable coronary artery disease (CAD) or ACS [26,27].…”

Phytosterols, Phytostanols, and Lipoprotein Metabolism

“…In some studies, phytosterols and phytostanols have modestly reduced serum triglyceride levels especially in those subjects with slightly increased baseline concentrations [ 23 , 24 ]. Lipoprotein (a) concentration remains unchanged [ 9 , 25 ], and phytostanols do not affect serum proprotein convertase subtilisin/kexin type 9 concentration [ 26 ].…”

Naturally Occurring PCSK9 Inhibitors

“…Simonen et al, in a randomized controlled double-blind trial in normal and hypercholesterolemic subjects, evaluated the effect of a 6 months consumption of vegetable-oil spread (20 g/day), enriched (plant stanol group) or not (control group) with plant stanols (3 g/day) as ester. The long-term intake of plant stanol esters reduced LDL-C by 7-10%, without affecting either PCSK9 plasma concentrations or the hepatic LDLR levels, indicating that plant stanol esters can lower LDL-C through inhibition of cholesterol absorption, without interfering with PCSK9 metabolism [46]. De Smet et al showed that an acute intake of plant stanol esters (0.25 mg cholesterol + 50 mg plant stanol esters dissolved in olive oil) in mice up-regulated mRNA expression of intestinal PCSK9 and LDLR, and their main transcription factor SREBP-2, whereas hepatic expression of these genes was down-regulated after 15 min following oral intake.…”