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Volume 29, No 2, Feb 2019

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 29 Issue 2, February 2019: 151-166

ORIGINAL ARTICLES

Blocking FSH inhibits hepatic cholesterol biosynthesis and reduces serum cholesterol

Yanjing Guo 1,2,3, Meng Zhao 1,2,3, Tao Bo 4, Shizhan Ma 1,2,3, Zhongshang Yuan 5, Wenbin Chen 4, Zhao He 2,3, Xu Hou 4, Jun Liu 6,Zhenhai Zhang 6, Qiang Zhu 7, Qiangxiu Wang 8, Xiaoyan Lin 8, Zhongli Yang 9, Min Cui 9, Lu Liu 1,2,3, Yujie Li 1,2,3, Chunxiao Yu 1,2,3, Xiaoyi Qi 1,2,3, Qian Wang 1,2,3, Haiqing Zhang 1,2,3, Qingbo Guan 1,2,3, Lifang Zhao 1,2,3, Shimeng Xuan 1,2,3, Huili Yan 1,2,3, Yanliang Lin 4, Li Wang 10, Qihang Li 1,2,3, Yongfeng Song 1,2,3,10, Ling Gao 3,4 and Jiajun Zhao 1,2,3

1 Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, 250021 Jinan, Shandong, China; 2 Shandong Key Laboratory of Endocrinology and Lipid Metabolism, 250021 Jinan, Shandong, China; 3 Institute of Endocrinology and metabolism, Shandong Academy of Clinical Medicine, 250021 Jinan, Shandong, China; 4 Scientific Center, Shandong Provincial Hospital Affiliated to Shandong University, 250021 Jinan, Shandong, China; 5 Department of Biostatistics, School of Public Health, Shandong University, 250012 Jinan, Shandong, China; 6 Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, 250021 Jinan, Shandong, China; 7 Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong University, 250021 Jinan, Shandong, China; 8 Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong University, 250021 Jinan, Shandong, China; 9 Department of Gynecology, Shandong Provincial Hospital Affiliated to Shandong University, 250021 Jinan, Shandong, China and 10 Department of Physiology and Neurobiology, and Institute for Systems Genomics, University of Connecticut, Storrs, CT 06269, USA Correspondence: Yongfeng Song (syf198506@163.com) or Ling Gao (linggao@sdu.edu.cn) or Jiajun Zhao (jjzhao@sdu.edu.cn, jjzhao@medmail.com.cn)

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.


https://doi.org/10.1038/s41422-018-0123-6

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