LAUSR

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 found that blocking FSH reduced serum cholesterol via inhibiting hepatic cholesterol biosynthesis. First, the epidemiological results showed that the serum FSH levels were positively correlated with the serum total cholesterol levels, even after excluding serum estrogen effects. In addition, the prevalence of hypercholesterolemia was significantly higher in peri-menopausal women than that in pre-menopausal women. Furthermore, we generated an FSH-elevated mouse model by intraperitoneal injection of exogenous FSH in ovariectomized (OVX) mice, in which a normal level of estrogen (E2) was maintained by exogenous supplementation. Consistently, the results indicated that FSH, independent of estrogen, increased the serum cholesterol level in the FSH-elevated mouse model. Moreover, blocking FSH by FSHβ-antibody or ablating the FSH receptor (FSHR) gene could effectively prevent hypercholesterolemia induced by FSH injection or high-cholesterol diet feeding. Mechanistically, FSH, binding with hepatic FSHRs, activated the Gi2a/β-arrestin-2/Akt pathway and subsequently inhibited the binding of FoxO1 with the SREBP-2 promoter, thus preventing FoxO1 from repressing SREBP-2 gene transcription. This effect, in turn, resulted in the upregulation of SREBP-2, which drove HMGCR nascent transcription and de novo cholesterol biosynthesis, leading to the increase of cholesterol accumulation. This study uncovers a new opportunity for treating hypercholesterolemia during menopause by blocking FSH signaling, particularly for women in peri-menopause characterized by only FSH elevation.