Abstract
Plasma levels of PCSK9 are significantly higher in postmenopausal women. Pharmacologically increased estrogen levels have been shown to lower PCSK9 and LDL-C levels in animals and humans. The action of estrogen suggests that it has the ability to prevent PCSK9-mediated LDLR degradation in liver cells. However, little is known about how estrogen alters PCSK9-mediated LDLR degradation. Here, we report that 17β-estradiol (βE2) reduces PCSK9-mediated LDLR degradation by a mechanism that involves activation of the G protein-coupled estrogen receptor (GPER). In cultured HepG2 cells, βE2 prevented the internalization of PCSK9, which subsequently lead to PCSK9-mediated LDLR degradation. The altered LDLR levels also resulted in an increase in LDL uptake that was not observed in the absence of PCSK9. In addition, we showed that clathrin was rapidly increased in the presence of PCSK9, and this increase was blocked by βE2 incubation, suggesting rapid recruitment of clathrin in HepG2 cells. PLCγ activation and intracellular Ca2+ release were both increased due to the rapid effect of estrogen. By using a GPER antagonist G15, we demonstrated that the GPER mediates the action of estrogen. Together, the data from this in vitro study demonstrate that estrogen can regulate LDLR levels mainly through GPER activation, which prevents PCSK9-dependent LDLR degradation in HepG2 cells.
Highlights
Estrogen plays a role in lipid metabolism in both physiological and pharmacological contexts
Several studies have been reported to suggest that estrogen regulates lipoprotein metabolism through the G protein-coupled estrogen receptor (GPER) in human
The results presented here provide data in support of this hypothesis, i.e., that the effect of βE2 regulation of LDLR is dependent upon extracellular proprotein convertase subtilisin/kexin type 9 (PCSK9)
Summary
Estrogen plays a role in lipid metabolism in both physiological and pharmacological contexts. Estrogen replacement therapy is still controversial, and supplements with a high dose of estrogen plus progestin or estrogen alone have been associated with a high risk of developing breast cancer [6,7,8,9]. A large randomized trial [10] from the Women’s Health Initiative (WHI) indicates that estrogen plus progestin is not beneficial in postmenopausal women; there is early harm for coronary heart disease (CHD) as well as continuing harm for stroke and venous thromboembolic events (VTE). Estrogen administered to postmenopausal women increases LDL clearance and lowers the levels of total cholesterol (TC), LDL-C, and apoliprotein B in plasma, showing the beneficial effects of estrogen in reducing the risk of cardiovascular disease [14,15,16,17,18,19,20,21]
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