Follicle-Stimulating Hormone Induces Postmenopausal Dyslipidemia Through Inhibiting Hepatic Cholesterol Metabolism J Clin Endocrinol Metab 101: 254–263, 2016 R3 이지훈 / Prof. 김성운

Background Postmenopausal Dyslipidemia Total cholesterol (TC) Low-density lipoprotein cholesterol (LDL-C) → Independent risk factors of cardiovascular diseases in postmenopausal years Dyslipidemia Fact Sheet in Korea 2015, Korea Society of Lipidology and Atherosclerosis Dyslipidemia Hyper-LDL- cholesterolemia

Background Follicle-Stimulating Hormone (FSH)

Methods and Materials Subjects and HRT 400 postmenopausal healthy women Age years Underwent HRT FSH (median value[50 th percentile], 78.3 IU/L) Group Ⅰ : FSH<78.3 IU/L Group Ⅱ : FSH≥78.3 IU/L HRT regimen 1mg estradiol daily and 10mg dydrogesterone for 10 days each month for 12 consecutive months

Methods and Materials Blood test Fasting morning ( h) Centrifuged withing 1 hour and stored at -80 ℃ Serum level of FSH, estradiol, TC, and LDL-C before HRT treatment Basal line The first to the third day of the “menstrual cycle” at the 13 th month

Methods and Materials Collection of human liver and ovarian samples Liver samples From postmenopausal female patients with hepatectomy At least 1cm from the tumor margin Diagnosed as normal by pathologists Ovary samples From postmenopausal female patients with adnexectomy Diagnosed as normal by pathologists

Methods and Materials Animal experiments Forty C57BL/6 mice 1)Sham (placebo) operation (SHAM) 2)Ovariectomy (OVX) 3)OVX + GnRH agonist (GnRHa) GnRHa → pituitary desensitization → inhibit pituitary gonadotropin secretion 4)OVX + GnRHa + FSH

Methods and Materials 1.Quantitative real-time PCR analysis 2.Western blot analysis 3.Tissue immunohistochemistry and cell immunofluorescence analysis 4.RNA interference experiments

Methods and Materials Quantitative real-time PCR analysis FSH receptor (FSHR) LDL receptor (LDLR) GAPDH (Glyceraldehyde-3-phosphate dehydrogenase) : housekeeping gene HMG coenzyme A reductase (HMGCR) : produce cholesterol cholesterol 7-hydroxylase (CYP7A1) : convert cholesterol to bile acid Western blot analysis anti FSHR anti LDLR anti GAPDH Tissue immunohistochemistry and cell immunofluorescence analysis RNA interference experiments

Results

The parameters of patients at baseline

Results Lipid response to decreasing levels of FSH Mean FSH concentration at baseline : IU/L After HRT… FSH decreased by 29.6% TC decreased by 3.7% (0.19 mmol/L) (P<0.05) LDL-C decreased by 4.4% (0.12 mmol/L) (P<0.05) Estradiol increased by pmol/L (P<0.05) BMI did not change significantly

Results The parameters of patients at baseline

Results Lipid response to decreasing levels of FSH

Results FSH effect on LDL-C metabolism in mice

Results FSH effect on LDL-C metabolism in mice

Results FSH effect on LDL-C metabolism in mice HMG coenzyme A reductase (HMGCR) → produce cholesterol LDL receptor (LDLR) cholesterol 7-hydroxylase (CYP7A1) → convert cholesterol to bile acid

Results Expression of FSHR in liver tissue

Results Expression of FSHR in liver tissue

Results Expression of FSHR in liver tissue

Results FSH decreased LDLR expression in HepG2 via FSHR

Results FSH decreased LDLR expression in HepG2 via FSHR

Results

Conclusion FSH may interact with its receptors in hepatocytes and reduce LDLR levels, which subsequently attenuates the endocytosis of LCL-C, resulting in an elevated circulating LDL-C level FSH