Role of PCSK9 in lipid metabolic disorders and ovarian dysfunction in polycystic ovary syndrome.

Abstract

BACKGROUND\nProprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in the cholesterol metabolism by negatively regulating the low-density lipoprotein receptor (LDLR). Lipid metabolic and ovarian disorders are the common clinical manifestation of polycystic ovary syndrome (PCOS). Here, we intended to elucidate the role of PCSK9 in the pathogenesis of PCOS conducted on a human population in case-control design and animal part in an interventional study.\n\n\nMETHODS\nWe firstly investigated the serum levels of PCSK9 in 46 PCOS patients compared with 49 healthy women as controls, and then developed a PCOS mouse model induced by dehydroepiandrosterone (DHEA) and a high-fat diet (HFD) to determine the role of PCSK9 in abnormal lipid metabolism and ovarian dysfunction of PCOS in four groups (n\u202f=\u202f40 per group): control, PCOS mice, PCOS plus alirocumab group, and PCOS plus vehicle group. The expression of PCSK9 in their serum, hepatic and ovarian tissues, serum lipid profiles and hormones were measured. Additionally, mRNA and protein expression levels of LDLR in hepatic and ovarian tissues, ovarian morphology and function were determined. Finally, we used freshly isolated theca-interstitial cells (TICs) and granulosa cells (GCs) from prepubertal normal mice to explore the effect of PCSK9 on LDL uptake of the cells.\n\n\nRESULTS\nSerum PCSK9 concentrations were higher in PCOS patients than normal controls (P\u202f<\u202f0.05). The PCOS model mice exhibited significantly increased serum levels of total cholesterol (TC), LDL-C and high-density lipoprotein-cholesterol (HDL-C; P\u202f<\u202f0.001, P\u202f<\u202f0.001, P\u202f=\u202f0.0004, respectively). Moreover, the serum PCSK9 protein level was significantly increased in PCOS mice (P\u202f=\u202f0.0002), which positively correlated with serum LDL-C (r =\u202f0.5279, P\u202f=\u202f0.0004) and TC (r\u202f=\u202f0.4151, P\u202f=\u202f0.035). In both liver and ovary of PCOS mice, PCSK9 mRNA and protein levels were significantly increased (P\u202f<\u202f0.05), but LDLR levels were significantly decreased (P\u202f<\u202f0.05). Furthermore, alirocumab inhibiting PCSK9 partly increased in LDLR expression in both liver and ovary in PCOS mice, also ameliorated the lipid metabolic disorders and pathological changes of ovarian morphology and function and serum reproductive hormones but not in the PCOS plus vehicle group. In vitro experiment, recombinant PCSK9 decreased LDL uptake in TICs and GCs (P\u202f<\u202f0.001, P\u202f=\u202f0.0011, respectively), which were partly reversed by alirocumab (P\u202f<\u202f0.001, P\u202f=\u202f0.012, respectively).\n\n\nCONCLUSION\nAbnormal high expression of PCSK9 in the blood, liver and ovary may be involved in the pathogenesis of PCOS by affecting lipid metabolism and ovarian function, and the inhibition of PCSK9 may partly reverse the pathological changes of PCOS. Our research suggests a possibility of PCSK9 as a new attractive target for diagnosis and treatment of PCOS.