Regulation of lipid droplets via the PLCβ2-PKCα-ADRP pathway in granulosa cells exposed to cadmium
Regulation of lipid droplets via the PLCβ2-PKCα-ADRP pathway in granulosa cells exposed to cadmium
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DOI：
10.1016/j.envpol.2020.115541
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发表时间：
2020-12-01
影响因子：
8.9
通讯作者：
Zhang, Qihao
中科院分区：
文献类型：
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作者：
Liu, Qunxing;Liang, Yuqing;Zhang, Qihao
在类固醇生成细胞中，类固醇是由储存在脂滴 (LD) 中的胆固醇从头合成的。脂肪分化相关蛋白（ADRP）调节的LD大小与胆固醇酯水解密切相关。许多研究报告称，镉 (Cd) 对颗粒细胞 (GC) 中的类固醇生成具有双重作用。然而，LD 的作用及其在 Cd 暴露引起的异常类固醇生成中的调节仍不清楚。在本研究中，雌性大鼠在妊娠和哺乳期间暴露于CdCl2，并研究了这种暴露对雌性后代卵巢GC的影响。发现 LD 的大小比 GC 中的正常大小小得多； ADRP 下调，激素敏感脂肪酶 (HSL) 磷酸化增加，随后类固醇生成急性调节蛋白 (StAR) 和胆固醇侧链裂解酶 (CYP11A1) 上调；随着ADRP的下调，1磷脂酰肌醇4,5-二磷酸磷酸二酯酶β2（PLCβ2）和蛋白激酶Cα型（PKCa）的表达均下降。这一系列事件导致血清中黄体酮水平升高。在体外用 20 mM CdCl2 处理 24 小时的 GC 中也得到了类似的结果。 PLC beta 2/PKCa基因沉默后ADRP的蛋白水平降低，PLC beta 2/PKC alpha/ADRP的敲低导致微米级LD的形成。我们发现镉暴露通过抑制 PLC beta 2-PKC alpha 信号通路下调 ADRP，减小 LD 的大小，并促进 HSL 磷酸化。胆固醇酯水解后，StAR 和 CYP11A1 均上调，从而导致黄体酮的大量产生。因此，LD 是 Cd 影响卵巢 GC 中类固醇激素合成的靶亚细胞器。这些发现可能有助于揭示镉污染引起卵巢功能障碍和性早熟的机制。 (C) 2020 Elsevier Ltd. 保留所有权利。
In steroidogenic cells, steroids are synthesized de novo from cholesterol stored in lipid droplets (LDs). The size of LDs regulated by adipose differentiation-related protein (ADRP) is closely related to cholesterol ester hydrolysis. Many studies reported that cadmium (Cd) had dual effects on steroidogenesis in granulosa cells (GCs). However, the role of LD and its regulation in abnormal steroidogenesis caused by Cd exposure remain unknown. In current study, female rats were exposed to CdCl2 during gestation and lactation, and influence of such exposure was investigated in ovarian GCs of female offspring. The size of LDs was found much smaller than normal in GCs; ADRP was down-regulated and hormone-sensitive lipase (HSL) phosphorylation was increased, followed by up-regulation of steroidogenic acute regulatory protein (StAR) and cholesterol side-chain cleavage enzyme (CYP11A1); the expression of 1phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-2 (PLC beta 2) and protein kinase C alpha type (PKCa) were both decreased accompanying the ADRP down-regulation. This series of events resulted in a high level of progesterone in serum. Similar results were demonstrated in GCs treated with 20 mM CdCl2 for 24 h in vitro. The protein level of ADRP was decreased after gene silencing of PLC beta 2/PKCa, and the knockdown of PLC beta 2/PKC alpha/ADRP led to micro-sized LD formation. We found that Cd exposure down-regulated ADRP by inhibiting the PLC beta 2-PKC alpha signaling pathway, reduced the size of LDs, and promoted HSL phosphorylation. StAR and CYP11A1 were both up-regulated following the hydrolysis of cholesterol ester, which led to a high production of progesterone. LD thereby is a target subcellular organelle for Cd to affect steroid hormone synthesis in ovarian GCs. These findings might help to uncover the mechanism of ovarian dysfunction and precocious puberty caused by Cd pollution. (C) 2020 Elsevier Ltd. All rights reserved.