Follicle-Stimulating Hormone Induces Postmenopausal Dyslipidemia Through Inhibiting Hepatic Cholesterol Metabolism

Song, Yang; Wang, En-Sheng; Xing, Lili; Shi, Shuai; Qu, Fan; Zhang, Dan; Li, Jingyi; Shu, Jing; Meng, Yahan; Sheng, Jian‐Zhong; Zhou, Jianhong; Huang, He‐Feng

doi:10.1210/jc.2015-2724

Cited by 92 publications

(132 citation statements)

References 35 publications

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“…Further supporting the therapeutic potential of FSHRCER T-cells, we confirmed that only tumor-free ovaries, and not any other healthy human tissues tested, expressed FSHR at the mRNA level ( Figure 3a ). Of note, this includes liver tissue, where a recent report has suggested possible expression of FSHR in tissue surrounding a hepatocellular carcinoma (35). …”

Section: Resultsmentioning

confidence: 99%

Follicle-Stimulating Hormone Receptor Is Expressed by Most Ovarian Cancer Subtypes and Is a Safe and Effective Immunotherapeutic Target

Perales‐Puchalt

Svoronos

Rutkowski

et al. 2017

Clinical Cancer Research

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Purpose Define the safety and effectiveness of T-cells re-directed against Follicle-Stimulating Hormone Receptor (FSHR)-expressing ovarian cancer cells. Experimental Design FSHR expression was determined by Western-blot, immunohistochemistry and Q-PCR in 77 human ovarian cancer specimens from 6 different histological subtypes and 20 human healthy tissues. The effectiveness of human T-cells targeted with full-length FSH in vivo was determined against a panel of patient-derived xenografts. Safety and effectiveness were confirmed in immunocompetent tumor-bearing mice, using constructs targeting murine FSHR and syngeneic T-cells. Results FSHR is expressed in gynecologic malignancies of different histological types, but not in non-ovarian healthy tissues. Accordingly, T-cells expressing full-length FSHR-re-directed chimeric receptors mediate significant therapeutic effects (including tumor rejection) against a panel of patient-derived tumors in vivo. In immunocompetent mice growing syngeneic, orthotopic, and aggressive ovarian tumors, fully murine FSHR-targeted T-cells also increased survival without any measurable toxicity. Notably, chimeric receptors enhanced the ability of endogenous tumor-reactive T-cells to abrogate malignant progression upon adoptive transfer into naïve recipients subsequently challenged with the same tumor. Interestingly, FSHR-targeted T-cells persisted as memory lymphocytes without noticeable PD-1-dependent exhaustion during end-stage disease, in the absence of tumor cell immunoediting. However, exosomes in advanced tumor ascites diverted the effector activity of this and other chimeric receptor-transduced T-cells away from targeted tumor cells. Conclusions T-cells redirected against FSHR+ tumor cells with full-length FSH represent a promising therapeutic alternative against a broad range of ovarian malignancies, with negligible toxicity even in the presence of cognate targets in tumor-free ovaries.

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Section: Resultsmentioning

confidence: 99%

Follicle-Stimulating Hormone Receptor Is Expressed by Most Ovarian Cancer Subtypes and Is a Safe and Effective Immunotherapeutic Target

Perales‐Puchalt

Svoronos

Rutkowski

et al. 2017

Clinical Cancer Research

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“…Postmenopausal status is characterized by high levels of FSH and LH, as well as low levels of E2, making it difficult to explore the precise role of FSH in renal function in the OVX mouse model. To diminish the potential effect of these two parameters, we used GnRHa‐treated ovariectomized mice administered with recombinant FSH in accordance with several studies (Li, Chen, et al, ; Song et al, ). Given that kidney injury is a relatively chronic process, we increased the dose of FSH from 0.15 IU to 0.3 IU and lengthened intervention time to 6 weeks, which was different from Liu's study on fat accumulation.…”

Section: Discussionmentioning

confidence: 99%

“…A substantial elevation in the serum follicle‐stimulating hormone level, although likely to compensate for estrogen withdrawal, has been closely involved in the adverse effects of menopause on many nongonadal tissues, including bone (Sponton & Kajimura, ), liver (Song et al, ), adipose tissue (Liu et al, ), umbilical vascular endothelial cell (Siraj et al, ), and biliary epithelium (Onori et al, ). Functional follicle‐stimulating hormone receptors (FSHRs) were also reported to exist in these extragonadal tissues to regulate bone, glucose, and lipid metabolism (Qi et al, ; Sun et al, ).…”

Section: Introductionmentioning

confidence: 99%

Follicle‐stimulating hormone promotes renal tubulointerstitial fibrosis in aging women via the AKT/GSK‐3β/β‐catenin pathway

et al. 2019

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Estrogen withdrawal in aging women contributes to the progression of chronic kidney disease (CKD). However, the effect of high circulating follicle‐stimulating hormone (FSH) levels on renal dysfunction remains unknown. In this study, blood samples from 3,055 postmenopausal women were collected and tested, which showed that there was a strong negative correlation between eGFR and FSH levels (p < 0.001), independent of LH, testosterone, and estradiol. Functional FSHR was detected in renal tubular epithelial cells. In vivo, high circulating FSH levels promoted a phenotype of tubulointerstitial fibrosis, characterized by increases in 24‐hr urine protein/creatinine ratio, serum Cr, serum BUN, and ECM deposition. Similar results obtained from cultured HK‐2 cells showed that FSH increased the transcriptional and protein expression of profibrotic mediators (collagen IV, fibronectin, and PAI‐1). This promotion of fibrosis by FSH occurred through the activation of AKT/GSK‐3β/β‐catenin pathway, which could be attenuated by silencing FSHR by siRNA or by LY294002 or MK2206. In addition, FSH‐stimulated HK‐2 cells secreted IL‐8, which promoted macrophage migration to exacerbate tubulointerstitial fibrosis. These results revealed a previously unknown effect of FSH on kidney injury, which may offer a critical insight into the development of CKD in aging postmenopausal women.

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“…However, recent studies have shown that FSHR can exist in extragonadal tissues, including the various locations of the female reproductive tract [16,31], the developing placenta [32], tumor vasculature and metastases [33] and other locations [34,35]. mRNA and protein of FSHR wild type or its variants are also expressed in bovine granulosa cells [36] and in the blood vessels of human malignant tumors [22].…”

Section: Fshr Expression In Extragonadal Tissuesmentioning

confidence: 99%

“…An earlier study found the placental growth defects and fetal loss were associated with FSHR expression in mice [32]. Additionally, FSHR may be involved in expressing the low-density lipoprotein receptor and regulating low-density lipoprotein cholesterol clearance in liver tissues [35]. Currently, it remains unclear whether these FSHR are structurally similar to those primarily expressed in the gonad tissues, and it is vital that the physiological functions of FSHR extragonadal expressions are clearly identified.…”

Section: Fshr Expression In Extragonadal Tissuesmentioning

confidence: 99%

Expression Levels of Follicle-Stimulating Hormone Receptor and Implication in Diagnostic and Therapeutic Strategy of Ovarian Cancer

et al. 2018

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Background: Follicle-stimulating hormone receptor (FSHR) has been shown to be expressed in ovarian cancer. Methods: Here we have summarized the potential therapeutic and diagnostic implication of FSHR in the ovarian cancers based on a review of the literature. Results: Current research indicates that FSHR comprises several variants: FSHR-1, FSHR-2, FSHR-3 and FSHR-4. Only FSHR-1 and FSHR-3 have biological roles. Although the level of FSHR differs in ovarian cancer tissues, few quantitative correlations have so far been reported on the expression levels of FSHR and carcinogenesis and progression of cancers. Conclusion: A comprehensive understanding of the role of FSHR in the ovarian cancers may help the search for novel therapeutic and diagnostic regimens and improve the management of cancer patients.

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Follicle-Stimulating Hormone Induces Postmenopausal Dyslipidemia Through Inhibiting Hepatic Cholesterol Metabolism

Abstract: 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.

Cited by 92 publications

References 35 publications

Follicle-Stimulating Hormone Receptor Is Expressed by Most Ovarian Cancer Subtypes and Is a Safe and Effective Immunotherapeutic Target

Follicle-Stimulating Hormone Receptor Is Expressed by Most Ovarian Cancer Subtypes and Is a Safe and Effective Immunotherapeutic Target

Follicle‐stimulating hormone promotes renal tubulointerstitial fibrosis in aging women via the AKT/GSK‐3β/β‐catenin pathway

Expression Levels of Follicle-Stimulating Hormone Receptor and Implication in Diagnostic and Therapeutic Strategy of Ovarian Cancer

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