The Cholesterol Metabolite 25-Hydroxycholesterol Activates Estrogen Receptor α-Mediated Signaling in Cancer Cells and in Cardiomyocytes

BackgroundThe hydroxylated derivatives of cholesterol, such as the oxysterols, play important roles in lipid metabolism. In particular, 25-hydroxycholesterol (25HC) has been implicated in a variety of metabolic events including cholesterol homeostasis and atherosclerosis. 25HC is detectable in human plasma after ingestion of a meal rich in oxysterols and following a dietary cholesterol challenge. In addition, the levels of oxysterols, including 25HC, have been found to be elevated in hypercholesterolemic serum.
Methodology/Principal FindingsHere, we demonstrate that the estrogen receptor (ER) α mediates gene expression changes and growth responses induced by 25HC in breast and ovarian cancer cells. Moreover, 25HC exhibits the ERα-dependent ability like 17β-estradiol (E2) to inhibit the up-regulation of HIF-1α and connective tissue growth factor by hypoxic conditions in cardiomyocytes and rat heart preparations and to prevent the hypoxia-induced apoptosis.
Conclusions/SignificanceThe estrogen action exerted by 25HC may be considered as an additional factor involved in the progression of breast and ovarian tumors. Moreover, the estrogen-like activity of 25HC elicited in the cardiovascular system may play a role against hypoxic environments.

研究背景：胆固醇的羟基化衍生物（如氧固醇（oxysterols））在脂质代谢中发挥关键调控作用。其中，25-羟胆固醇（25-hydroxycholesterol, 25HC）已被证实参与包括胆固醇稳态、动脉粥样硬化在内的多种代谢过程。在进食富含氧固醇的膳食以及膳食胆固醇负荷后，人体血浆中可检测到25HC。此外，研究发现高胆固醇血症患者血清中，包括25HC在内的氧固醇水平均显著升高。
方法学/主要研究结果：本研究证实，雌激素受体（ER）α可介导25HC在乳腺癌与卵巢癌细胞中诱导的基因表达变化及生长应答。此外，25HC与17β-雌二醇（17β-estradiol, E2）一样，具备依赖于ERα的活性：可在心肌细胞与大鼠心脏组织标本中，抑制缺氧条件下缺氧诱导因子-1α（HIF-1α）与结缔组织生长因子的上调表达，并阻断缺氧诱导的细胞凋亡。
结论与意义：25HC所介导的雌激素样作用，可被视为参与乳腺与卵巢肿瘤进展的额外调控因素。此外，25HC在心血管系统中诱导的雌激素样活性，或可发挥对抗缺氧环境的作用。