Biochemical and Biophysical Research Communications, Vol.503, No.1, 8-13, 2018
Hyperhomocysteinemia and hyperandrogenemia share PCSK9-LDLR pathway to disrupt lipid homeostasis in PCOS
Women with polycystic ovary syndrome (PCOS) are at increased risk of cardiovascular diseases (CVD); however, the independent role of PCOS in the incident CVD remains unknown. There are reports that hyperhomocysteinemia (HHcy), a potential cause of CVD, is frequently associated with PCOS. The present study investigates the independent attributes of hyperandrogenemia (HA), the integral associate of PCOS, and HHcy in causing atherogenic dyslipidemia. Twenty-five-day old rats were treated with homocysteine (Hcy) at 50 mg/kg/day dose level for 12 weeks. The HepG2 cell lines transfected with siRNA directed to PCSK9 were challenged with Hcy, homocysteine thiolactone (HTL), testosterone, 5 alpha-dihydroxytestosterone (5 alpha-DHT), or estradiol for 24 h. Rats administered with Hcy developed HHcy and displayed PCOS-like phenotypes with adversely altered lipid homeostasis and attenuated PI3K-AKT and Wnt signalling cascade. Overexpression of steroidogenic acute regulatory protein (StAR) and down-regulated expression of Aromatase together with elevated testosterone level marked the state of HA. In culture, the HepG2 cells responded independently to Hcy, HTL, testosterone, and 5 alpha-DHT by an overt expression of PCSK9 and down-regulated expression of LDLR. The effect was magnified under the combined influence of Hcy and androgen(s). Estradiol, by contrast, exhibited the reverse effect. The findings suggest that HA may independently attribute to an increased cardiovascular risk in PCOS; however, the coexistence of HHcy catalyzes the risk further. (C) 2018 Published by Elsevier Inc.