Cadmium facilitates the formation of large lipid droplets via PLCβ2-DAG-DGKε-PA signal pathway in Leydig cells.
Cadmium facilitates the formation of large lipid droplets via PLCβ2-DAG-DGKε-PA signal pathway in Leydig cells.
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DOI：
10.1016/j.ecoenv.2023.115610
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发表时间：
2023-10
影响因子：
6.8
通讯作者：
Youjin Wang;Yuqing Liang;Zansheng Yuan;Wanwen Mai;Yang Leng;Runze Zhang;Jiayan Chen;Caiyong Lai;Hongxia Chen;Xiaoping Wu;Chao Sheng;Qihao Zhang
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作者：
Youjin Wang;Yuqing Liang;Zansheng Yuan;Wanwen Mai;Yang Leng;Runze Zhang;Jiayan Chen;Caiyong Lai;Hongxia Chen;Xiaoping Wu;Chao Sheng;Qihao Zhang
镉（Cd）暴露会损害生殖系统。脂滴在类固醇生成细胞中发挥着重要作用，为类固醇激素提供原料。我们发现间质细胞暴露于Cd后的LDs比正常细胞大，但其对甾体生成的影响及其潜在机制尚不清楚。利用Isobaric tag for relative and absolute quantitation （iTARQ）蛋白质组学方法，研究人员发现，暴露于母体Cd的雄性大鼠的未成熟间质细胞（ILCs）和成年间质细胞（ALCs）中，磷酸化二酯酶β -2 （plc - β2）是上调幅度最大的蛋白。与plc - β2的高表达一致，暴露于Cd的雄性大鼠间质细胞中，LDs的大小增加，同时胆固醇和孕酮（P4）水平降低。然而，高水平的PLCβ2并没有导致高水平的二酰基甘油（DAG），因为Cd暴露上调了二酰基甘油激酶ε (dgk)，促进了DAG向磷脂酸（PA）的转化。外源PA与Cd诱导的胞内PA浓度一致，有利于R2C细胞形成较大的LDs，并降低培养基中P4水平。当plc - β2表达下调后，Cd引起的DGKε升高逆转，PA水平降至正常水平。结果，大ld恢复到正常大小，总胆固醇水平得到改善，恢复类固醇生成。通过plc - β2- dag - dgkε信号通路调节PA的积累，可导致Cd暴露的雄性间质细胞形成较大的lld和类固醇激素合成不足。这些数据表明，lld是Cd诱导的雄性类固醇激素缺乏的重要靶细胞器。
Cadmium (Cd) exposure damages the reproductive system. Lipid droplets (LDs) play an important role in steroid-producing cells to provide raw material for steroid hormone. We have found that the LDs of Leydig cells exposed to Cd are bigger than those of normal cells, but the effects on steroidogenesis and its underlying mechanism remains unclear. Using Isobaric tag for relative and absolute quantitation (iTARQ) proteomics, phosphodiesterase beta-2 (PLCβ2) was identified as the most significantly up-regulated protein in immature Leydig cells (ILCs) and adult Leydig cells (ALCs) derived from male rats exposed to maternal Cd. Consistent with high expression of PLCβ2, the size of LDs was increased in Leydig cells exposed to Cd, accompanied by reduction in cholesterol and progesterone (P4) levels. However, the high PLCβ2 did not result in high diacylglycerol (DAG) level, because Cd exposure up-regulated diacylglycerol kinases ε (DGKε) to promote the conversion from DAG to phosphatidic acid (PA). Exogenous PA, which was consistent with the intracellular PA concentration induced by Cd, facilitated the formation of large LDs in R2C cells, followed by reduced P4 level in the culture medium. When PLCβ2 expression was knocked down, the increased DGKε caused by Cd was reversed, and then the PA level was decreased to normal. As results, large LDs returned to normal size, and the level of total cholesterol was improved to restore steroidogenesis. The accumulation of PA regulated by PLCβ2-DAG-DGKε signal pathway is responsible for the formation of large LDs and insufficient steroid hormone synthesis in Leydig cells exposed to Cd. These data highlight that LD is an important target organelle for Cd-induced steroid hormone deficiency in males.