β-estradiol adjusts intestinal function via ERβ and GPR30 mediated PI3K/AKT signaling activation to alleviate postmenopausal dyslipidemia
β-estradiol adjusts intestinal function via ERβ and GPR30 mediated PI3K/AKT signaling activation to alleviate postmenopausal dyslipidemia
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β-雌二醇通过 ERβ 和 GPR30 介导的 PI3K/AKT 信号激活调节肠道功能，缓解绝经后血脂异常
DOI：
10.1016/j.bcp.2020.114134
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发表时间：
2020-10-01
影响因子：
5.8
通讯作者：
Bian, Huimin
中科院分区：
文献类型：
--
作者：
Meng, Qinghai;Li, Jun;Bian, Huimin
雌激素分泌减少以及雌激素受体功能下降导致绝经后女性血脂异常和心血管疾病（CVD）的发病率增加。我们先前报道过，β - 雌二醇对双侧卵巢切除的载脂蛋白E（-/-）小鼠的脂质具有显著的调节作用。在本研究中，我们探讨了β - 雌二醇如何通过雌激素受体调节肠道功能以缓解绝经后血脂异常。卵巢切除的载脂蛋白E（-/-）小鼠接受β - 雌二醇治疗90天，我们发现β - 雌二醇降低了血清中总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL - c）、白细胞介素 - 1β（IL - 1β）和白细胞介素 - 18（IL - 18）的水平，并减少了肝脏中的脂质堆积。β - 雌二醇减轻了卵巢切除小鼠空肠的损伤和炎症，并促进了紧密连接相关蛋白的表达。此外，β - 雌二醇增加了卵巢切除小鼠空肠中雌激素受体α（ERα）、雌激素受体β（ERβ）、G蛋白偶联受体30（GPR30）和三磷酸腺苷结合盒转运体G5（ABCG5）蛋白的表达，并降低了尼曼 - 匹克C1型类似蛋白1（NPC1L1）和清道夫受体B1（SR - B1）的水平。在胆固醇孵育的Caco - 2细胞中，β - 雌二醇上调磷脂酰肌醇 - 3激酶/蛋白激酶B（PI3K/AKT）信号通路，减少胆固醇堆积，抑制炎症信号传导，并增加紧密连接相关蛋白的表达。抑制雌激素受体β或G蛋白偶联受体30会降低β - 雌二醇对胆固醇孵育的Caco - 2细胞中胆固醇堆积、紧密连接和炎症的保护作用，而同时沉默雌激素受体β和G蛋白偶联受体30则完全消除了β - 雌二醇的保护作用。抑制磷脂酰肌醇 - 3激酶/蛋白激酶B会消除β - 雌二醇对胆固醇堆积、紧密连接相关蛋白表达和炎症的保护作用，但对胆固醇孵育的Caco - 2细胞中雌激素受体α、雌激素受体β或G蛋白偶联受体30的表达没有影响。我们的研究结果提供了证据，表明β - 雌二醇通过雌激素受体β和G蛋白偶联受体30介导的磷脂酰肌醇 - 3激酶/蛋白激酶B信号通路激活来调节肠道功能，以缓解绝经后血脂异常。
Decreases in estrogen secretion and estrogen receptor function lead to an increase in the incidence of dyslipidemia and cardiovascular disease (CVD) in postmenopausal women. We previously reported that beta-estradiol has a significant regulatory effect on lipids in ApoE(-/-) mice with bilateral ovariectomy. In the present study, we investigated how beta-estradiol regulates intestinal function via estrogen receptors to alleviate postmenopausal dyslipidemia. Ovariectomized ApoE(-/-) mice were treated with beta-estradiol for 90 days, and we found that beta-estradiol reduced TC, TG, LDL-c, IL-1 beta and IL-18 levels in serum and decreased lipid accumulation in the liver. beta-estradiol reduced injury and inflammation in the jejunum in ovariectomized mice, and promoted the expression of tight junction-related proteins. Moreover, beta-estradiol increased ER alpha, ER beta, GPR30 and ABCG5 protein expression, and decreased the levels of NPC1L1 and SR-B1 in the jejunum of ovariectomized mice. In Caco-2 cells incubated with cholesterol, beta-estradiol up-regulated PI3K/AKT signaling, reduced cholesterol accumulation, suppressed inflammatory signaling, and increased the expression of tight junction-related proteins. ER beta or GPR30 inhibition decreased the protective effect of beta-estradiol on cholesterol accumulation, tight junctions, and inflammation in cholesterol incubated Caco-2 cells, while silencing both ER beta and GPR30 completely eliminated the protective effect of beta-estradiol. PI3K/AKT inhibition abolished the protective effect of beta-estradiol on cholesterol accumulation, tight junction-related protein expression, and inflammation, but had no influence on ER alpha, ER beta or GPR30 expression in cholesterol incubated Caco-2 cells. Our results provide evidence that beta-estradiol regulates intestinal function via ER beta and GPR30 mediated PI3K/AKT signaling activation to alleviate postmenopausal dyslipidemia.