Follicle-Stimulating Hormone Induces Postmenopausal Dyslipidemia Through Inhibiting Hepatic Cholesterol Metabolism
Follicle-Stimulating Hormone Induces Postmenopausal Dyslipidemia Through Inhibiting Hepatic Cholesterol Metabolism
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卵泡刺激素通过抑制肝脏胆固醇代谢诱发绝经后血脂异常
DOI：
10.1210/jc.2015-2724
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发表时间：
2016-01-01
影响因子：
5.8
通讯作者：
Huang, He-Feng
中科院分区：
文献类型：
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作者：
Song, Yang;Wang, En-Sheng;Huang, He-Feng
背景：更年期女性低密度脂蛋白胆固醇（LDL-C）升高与心血管疾病的高风险相关。目的：本研究的目的是探讨绝经后高 FSH 水平对血脂的影响及其机制。方法：检测 400 名中国绝经后女性的血清 FSH 和血脂水平。通过 PCR 和蛋白质印迹法鉴定肝脏和 HepG2 细胞中 FSH 受体 (FSHR) 的表达。通过使用带有或不带有额外 FSH 的 GnRH 激动剂来模拟不同的 FSH 状态，在卵巢切除小鼠模型中证实了 FSH 对脂质代谢的影响。 LDL受体（LDLR）是通过内吞作用清除LDL-C的必要因子，通过PCR和蛋白质印迹法检测。结果：血清FSH较高（基线时≥78.3 IU/L）的绝经后女性的血清总胆固醇和LDL-C水平高于FSH水平为40-78.3 IU/L的女性（P < .01）。在接受激素替代疗法治疗后，FSH 较高的女性组中总胆固醇和 LDL-C 水平的改善更为显着。只有在激素替代治疗后 FSH 水平降低超过 30% 的女性，血脂水平才会出现显着改善。卵巢切除小鼠的血清 FSH 和脂质水平较高，肝脏 LDLR 表达降低。在HepG2细胞中，FSH以剂量和时间依赖性方式抑制LDLR，并且用特异性siRNA敲低FSHR可逆转FSH诱导的较低LDLR。结论：FSH可能与其在肝细胞中的受体相互作用并降低LDLR水平，从而减弱LDL-C的内吞作用，导致循环LDL-C水平升高。
Context: The elevated low-density-lipoprotein cholesterol (LDL-C) in menopausal women is associated with higher risks of cardiovascular diseases.Objective: The aim of this study is to investigate the influence and mechanism by which high postmenopausal FSH levels affect lipid profiles.Methods: The serum FSH and lipid levels were examined in 400 Chinese postmenopausal women. The FSH receptor (FSHR) expression was identified in liver and HepG2 cells by PCR and Western blotting. The effects of FSH on lipid metabolism were confirmed in an ovariectomized mouse model by using GnRH agonist with or without additional FSH to mimic different FSH status. LDL receptor (LDLR), a necessary factor for clearance of LDL-C through endocytosis, was examined by PCR and Western blotting.Results: The postmenopausal women with higher serum FSH (>= 78.3 IU/L at baseline) had higher serum total cholesterol and LDL-C levels than those women with FSH levels of 40-78.3 IU/L (P < .01). The improvements of total cholesterol and LDL-C levels were more significant in higher FSH women group after treatment with hormone replacement therapy. It was only in the women whose FSH levels were reduced more than 30% after hormone replacement therapy who showed significant improvement of lipid levels. Ovariectomized mice had high serum FSH and lipids levels and reduced hepatic LDLR expression. In HepG2 cells, FSH inhibited the LDLR in a dose-and time-dependent manner, and the FSHR knockdown with specific siRNA reversed the lower LDLR induced by FSH.Conclusions: FSH may interact with its receptors in hepatocytes and reduce LDLR levels, which subsequently attenuates the endocytosis of LDL-C, resulting in an elevated circulating LDL-C level.