| Literature DB >> 30559440 |
Yanjing Guo1,2,3, Meng Zhao1,2,3, Tao Bo4, Shizhan Ma1,2,3, Zhongshang Yuan5, Wenbin Chen4, Zhao He2,3, Xu Hou4, Jun Liu6, Zhenhai Zhang6, Qiang Zhu7, Qiangxiu Wang8, Xiaoyan Lin8, Zhongli Yang9, Min Cui9, Lu Liu1,2,3, Yujie Li1,2,3, Chunxiao Yu1,2,3, Xiaoyi Qi1,2,3, Qian Wang1,2,3, Haiqing Zhang1,2,3, Qingbo Guan1,2,3, Lifang Zhao1,2,3, Shimeng Xuan1,2,3, Huili Yan1,2,3, Yanliang Lin4, Li Wang10, Qihang Li1,2,3, Yongfeng Song11,12,13,14, Ling Gao15,16, Jiajun Zhao17,18,19.
Abstract
Menopause is associated with dyslipidemia and an increased risk of cardio-cerebrovascular disease. The classic view assumes that the underlying mechanism of dyslipidemia is attributed to an insufficiency of estrogen. In addition to a decrease in estrogen, circulating follicle-stimulating hormone (FSH) levels become elevated at menopause. In this study, we find that blocking FSH reduces serum cholesterol via inhibiting hepatic cholesterol biosynthesis. First, epidemiological results show that the serum FSH levels are positively correlated with the serum total cholesterol levels, even after adjustment by considering the effects of serum estrogen. In addition, the prevalence of hypercholesterolemia is significantly higher in peri-menopausal women than that in pre-menopausal women. Furthermore, we generated a mouse model of FSH elevation by intraperitoneally injecting exogenous FSH into ovariectomized (OVX) mice, in which a normal level of estrogen (E2) was maintained by exogenous supplementation. Consistently, the results indicate that FSH, independent of estrogen, increases the serum cholesterol level in this mouse model. Moreover, blocking FSH signaling by anti-FSHβ antibody or ablating the FSH receptor (FSHR) gene could effectively prevent hypercholesterolemia induced by FSH injection or high-cholesterol diet feeding. Mechanistically, FSH, via binding to hepatic FSHRs, activates the Gi2α/β-arrestin-2/Akt pathway and subsequently inhibits the binding of FoxO1 with the SREBP-2 promoter, thus preventing FoxO1 from repressing SREBP-2 gene transcription. This effect, in turn, results in the upregulation of SREBP-2, which drives HMGCR nascent transcription and de novo cholesterol biosynthesis, leading to the increase of cholesterol accumulation. This study uncovers that blocking FSH signaling might be a new strategy for treating hypercholesterolemia during menopause, particularly for women in peri-menopause characterized by FSH elevation only.Entities:
Mesh：
Substances：
Year: 2018 PMID： 30559440 PMCID： PMC6355920 DOI： 10.1038/s41422-018-0123-6
Source DB: PubMed Journal: Cell Res ISSN： 1001-0602 Impact factor: 25.617