Blocking FSH inhibits hepatic cholesterol biosynthesis and reduces serum cholesterol

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 premenopausal 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.

FSH-metabolic circuitry and menopause

“…Furthermore, in contrast to our results where we did not find decrements in serum cholesterol after 8 weeks of anti-FSH antibody treatment (Liu et al 2017), the authors provide compelling evidence that blocking FSH action either through an anti-FSHβ antibody or in Fshr −/− mice significantly reduced serum and hepatic cholesterol content, without significantly altering estrogen levels (Guo et al 2019). The presence of the FSHR in the liver was also established in both human and mouse liver samples using RT-PCR, in situ hybridization and immunofluorescent labeling (Guo et al 2019). Finally, FSH was shown to upregulate liver HMG-CoA reductase, a rate-limiting enzyme for cholesterol biosynthesis; this effect appears to be regulated through the activation of the transcription factor sterol regulatory element-binding protein 2 (SREBP-2) (Pertusa et al 2007, Guo et al 2019.…”

“…To further substantiate a role for FSH in cholesterol metabolism, Guo et al used ovariectomized mice in which estrogen was clamped by exogenous administration. These mice, when injected with recombinant FSH, showed higher levels of serum TC and LDL-C, and elevated hepatic cholesterol biosynthesis (Guo et al 2019). Furthermore, in contrast to our results where we did not find decrements in serum cholesterol after 8 weeks of anti-FSH antibody treatment (Liu et al 2017), the authors provide compelling evidence that blocking FSH action either through an anti-FSHβ antibody or in Fshr −/− mice significantly reduced serum and hepatic cholesterol content, without significantly altering estrogen levels (Guo et al 2019).…”

“…These mice, when injected with recombinant FSH, showed higher levels of serum TC and LDL-C, and elevated hepatic cholesterol biosynthesis (Guo et al 2019). Furthermore, in contrast to our results where we did not find decrements in serum cholesterol after 8 weeks of anti-FSH antibody treatment (Liu et al 2017), the authors provide compelling evidence that blocking FSH action either through an anti-FSHβ antibody or in Fshr −/− mice significantly reduced serum and hepatic cholesterol content, without significantly altering estrogen levels (Guo et al 2019). The presence of the FSHR in the liver was also established in both human and mouse liver samples using RT-PCR, in situ hybridization and immunofluorescent labeling (Guo et al 2019).…”

“…However, there has been recent evidence that FSH might play a role in increasing hepatic cholesterol production, independent of serum estrogen. A recent study of 278 pre-and perimenopausal women found that serum FSH, total cholesterol (TC) and LDL cholesterol (LDL-C) levels were higher in the perimenopausal group compared with pre-menopausal women, despite similar serum estrogen levels (Guo et al 2019). Serum FSH levels displayed a positive correlation with TC and LDL-C after adjustment for estrogen.…”

“…The presence of the FSHR in the liver was also established in both human and mouse liver samples using RT-PCR, in situ hybridization and immunofluorescent labeling (Guo et al 2019). Finally, FSH was shown to upregulate liver HMG-CoA reductase, a rate-limiting enzyme for cholesterol biosynthesis; this effect appears to be regulated through the activation of the transcription factor sterol regulatory element-binding protein 2 (SREBP-2) (Pertusa et al 2007, Guo et al 2019. Another possible mechanism of elevated circulating LDL-C is the FSH-mediated reduction in hepatic LDL receptors which results in decreased endocytosis of LDL-C.…”