The role of proprotein convertase subtilisin/kexin type-9 concentration and paraoxonase 1 activities in the blood of women with polycystic ovary syndrome

Highlights

• For the first time, the serum PCSK9 concentration of Caucasian women with PCOS was determined.

• The women with PCOS were characterized by higher PCSK9 and lower HDL concentration than women without PCOS.

• The serum PCSK9 concentration in the group with PCOS could be associated with androgens and insulin level.

• Significant changes in serum paraoxonase activities were detected between women with and without PCOS.

Abstract

This study aimed to evaluate the concentration of proprotein convertase subtilisin/kexin type-9 (PCSK9) and the activities of paraoxonase 1 in women with and without polycystic ovary syndrome (PCOS). We found significant higher PCSK9, whereas lower high-density lipoprotein concentration in the serum of women with PCOS when compared to the group without PCOS. Also paraoxonase 1 activities were significantly different between women with PCOS than without PCOS. In addition, the women with PCOS and insulin resistance had higher concentrations of PCSK9 than women with PCOS and insulin sensitivity. Higher PCSK9 concentration in the group with PCOS could be also associated with hormones concentrations.

Changes in paraoxonase 1 activities and lipid profile parameters as well as higher concentration of PCSK9 in the group of women with PCOS could be associated with metabolism disorders, but due to the small clinical sample size, the study should be continued.

Introduction

Polycystic ovary syndrome (PCOS) is a set of multiple symptoms associated with many metabolic and endocrine disorders (Daghestani, 2018; Ebrahimi-Mamaghani et al., 2015). Its diagnosis is difficult and based mainly on the presence of oligo/anovulation, hyperandrogenemia, and/or detection of ovarian cysts (Pedersen et al., 2018). There is a close relationship between lipid profile parameters and ovarian function (Wang et al., 2019). Previous studies have shown that loss of ovarian function could be associated with higher triglyceride (TG) concentration and lower high-density lipoprotein cholesterol (HDL-C) concentration (Knauff et al., 2008). In addition, cholesterol, as a substrate source for steroid hormones, is crucial for ovarian endocrine (Hu et al., 2010; Wang et al., 2019). In the blood of women with PCOS, the lipid profile parameters show findings that could be associated with the hormonal disorders and increased risk of cardiovascular diseases (CVD) development (Pradas et al., 2019). Contemporary medicine links the risk of atherosclerotic CVD with elevated concentrations of TG and low-density lipoprotein cholesterol (LDL-C) (Authors/Task Force Members et al., 2019). At the same time, the role of HDL-C concentrations in CVD development is the opposite. Many epidemiological studies have shown an inverse correlation between HDL-C concentration and the development or progression of CVD (Li et al., 2019; Mahdy Ali et al., 2012). However, Mendelian randomization studies have not confirmed that lower HDL-C concentration was associated with higher CVD risk (Authors/Task Force Members et al., 2019). Furthermore, the newest study conducted by Tadecso et al. shown that higher risk of CVD development in the women with PCOS is not only associated with impairment of HDL but also with female hormonal status (Tedesco et al., 2019).

The latest guidelines for the management of dyslipidaemias have confirmed that one of the main initiating factors of atherogenesis is the retention of LDL-C (Authors/Task Force Members et al., 2019). Elevated LDL-C concentration could also be associated with proprotein convertase subtilisin/kexin type 9 (PCSK9) (Ruscica et al., 2017), which modulates plasma levels of LDL-C by promoting the degradation of LDL receptors (LDLRs). In addition, a direct role of PCSK9 in atherosclerotic plaque formation has been revealed (Macchi et al., 2019a). It has also been shown that statin treatment could increase PCSK9 level, which might be associated with further higher LDL-C concentration (Authors/Task Force Members et al., 2019; Macchi et al., 2019a; Raal et al., 2013). PCSK9 is a promising new target for preventing CV events, but it has not been recognized as a biomarker of CVD risk until recently. A study conducted by Macchi et al. (Macchi et al., 2019b) demonstrated that a higher concentration of PCSK9 in the serum of obese subjects was associated with Framingham Risk Score and environmental air pollution, whereas the prospective cohort study conducted by Ridker et al. shown that plasma PCSK9 concentration did not predict future CVD (Ridker et al., 2016). Earlier studies also confirmed a higher concentration of PCSK9 in plasma of women compared to men (Ferri and Ruscica, 2016). Moreover, postmenopausal women had significantly higher median plasma levels of PCSK9 than premenopausal women (Ruscica et al., 2017), which could be controlled by hormones such as estrogen (Ruscica et al., 2017; Zhang et al., 2019).

Another crucial parameter closely linked with lipid profile parameters is paraoxonase 1 (PON1), an enzyme structurally and functionally related to HDL (Litvinov et al., 2012; Shih and Lusis, 2009). Moreover, PON1 directly protects LDL against oxidative modification (Mackness et al., 2001). The hydrolytic activity of PON1 can be divided into three types: phosphotriesterase (paraoxonase), arylesterase and lactonase activities (Bizoń and Milnerowicz, 2018). Previous studies have shown that lower serum PON1 activity in pathological states such as non-alcoholic fatty liver disease, diabetes, familial hypercholesterolemia, and other diseases is associated with accelerated atherogenesis (Mackness et al., 2001; Wu et al., 2018). Reduced PON1 activity might elevate levels of oxidative stress altering the metabolism in PCOS patients (Kunjantarachot et al., 2020).

Both PCSK9 and PON1 are mainly expressed in the liver and play a crucial role in lipid profile parameters. Therefore this study aimed to evaluate the concentration of PCSK9 and lipid profile parameters and the activities of PON1 in women with and without PCOS. Furthermore, in the group with PCOS, the association of PCSK9 concentration and PON1 activities with selected biochemical and hormonal parameters was assessed.