Estrogen Mediates an Atherosclerotic-Protective Action via Estrogen Receptor Alpha/SREBP-1 Signaling

Abstract

Menopause is associated with dyslipidemia and an increased risk of cardiovascular disease, the underlying mechanism of dyslipidemia is attributed to an insufficiency of estrogen. In this study, we find that estrogen mediates an atherosclerotic-protective action via estrogen receptor alpha/SREBP-1 signaling. Increased lipid accumulation and low-density lipoprotein (LDL)-uptake in HepG2 cells and THP-1 macrophages were induced by treatment of mixed hyperlipidemic serum from postmenopausal women; 17β-estradiol [estrogen (E2)] (10 nM) administration significantly improved hyperlipidemic profiles, relieved fatty-liver damage and attenuated the plaque area in the heart chamber of high-fat diet (HFD)-fed ovariectomized (OVX) ApoE–/– mice. Expression of sterol regulatory element-binding protein (SREBP)-1 mRNA of circulating leukocytes in postmenopausal women was strongly correlated to the serum E2 level. Exploration of data from the Gene Expression Profiling Interactive Analysis (GEPIA) database revealed that expression of SREBP-1 protein correlated to expression of estrogen receptor (ESR)α protein in the liver, blood and in normal tissue. Genetic overexpression/inhibition of ESRα resulted in increased/decreased SREBP-1 expression as well as attenuated/deteriorated lipid deposition in vitro. An inhibitor of the protein kinase B/mammalian target of rapamycin (AKT/mTOR) pathway, AZD8055, abolished ESRα-induced SREBP-1 expression in HepG2 cells. Moreover, E2 and statin co-treatment significantly reduced lipid accumulation in vitro and hindered the progression of atherosclerosis and fatty-liver damage in OVX ApoE–/– mice. Collectively, our results suggest that estrogen could exerted its atherosclerotic-protective action via ESRα/SREBP-1 signaling. E2 might enhance the cellular sensitivity of statins and could be used as a novel therapeutic strategy against atherosclerotic disorders in postmenopausal women.

Prostate Cell Heterogeneity and Cxcl17 Upregulation in Mouse Steroid Hormone Imbalance

“…70 Estradiol also diminishes M2a activation in macrophages from males. 71 However, considering the complexity of an in viv o system, the direct effects of estradiol might be inferior to other paracrine factors on macrophages; the direct action of estradiol, for example, should inhibit foam cell formation by decreasing lipid accumulation in macrophages, as previously shown, 72 which contrasts with our observations in the male steroid hormone imbalance model. Another possibility is that local estrogen levels are highly variable in the tissue microenvironment, especially, when we compare tissue vs. intraluminal areas.…”

Unraveling the Role of Sex in Endothelial Cell Dysfunction: Evidence From Lineage Tracing Mice and Cultured Cells

“…Given that tamoxifen is a selective estrogen receptor modulator, 34,35 we employed nontamoxifen inducible Apoe –/– mice (C56B7/J genetic background) to ensure that differences in male and female EC-YFP Apoe –/– mice do not result from the tamoxifen treatment. Consistently, with the tamoxifen-inducible EC-YFP Apoe –/– mice, nontamoxifen-treated Apoe –/– female mice at the late stage of atherosclerosis had significantly lower body weight, cholesterol, and triglycerides (Table S2), and more extensive atherosclerotic lesions in aortic roots than male mice (Figure 4H).…”

Analysis of SIRT1 genetic variants in young Mexican individuals: relationships with overweight and obesity

“…This could also be explained by the protective role that female hormones play on atherosclerosis. Specifically, it has been described that estrogens modulate the atherosclerotic protective action through the signaling of the estrogen receptor alpha/SREBP-1, which is a transcription factor of genes related to lipid synthesis (Xie et al, 2022) and the potential of SREBP-1 to reduce fatty acid synthesis and enhance insulin secretion has been described in mice (Ruiz et al, 2014), Finally, current Mexican populations are genetically heterogenous as a consequence of migrations and cultural and lifestyle transitions, which contribute to the allele selection and diversity observed in Native American populations (Barquera et al, 2020). For example, one hypothesis mentions that some genes related to metabolic diseases could be the target of natural selection in humans (Rees et al, 2020), and the allelic frequencies of genetic variants such as SNVs could have been affected by the interbreeding derived from the European colonization of the American continent (Lindo et al, 2016).…”