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研究生:陳智傑
研究生(外文):Chih-Chieh Chen
論文名稱:皮質酮及乳酸調節大鼠萊氏細胞分泌睪酮的交互作用
論文名稱(外文):Interactive Effect of Corticosterone and Lactate on Regulation of Testosterone Production in Rat Leydig Cells
指導教授:王錫崗王錫崗引用關係
指導教授(外文):Paulus S. Wang
學位類別:博士
校院名稱:國立陽明大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2017
畢業學年度:105
語文別:中文
論文頁數:49
中文關鍵詞:睪酮皮質酮乳酸黃體生成素受體腺苷酸環化酶
外文關鍵詞:corticosteroneadenylyl cyclaseLeydig cellstestosteroneluteinizing hormone receptorlactate
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過去實驗證實,提升睾酮(testosterone)的濃度不但有助於運動員骨骼肌肉肥大同時也能夠提升運動訓練或比賽過程中成績的表現。然而,過度的運動訓練或壓力增加時會促進糖皮質素 (glucocorticoid) 濃度上升,進而減少雄性素 (androgen) 的生成。目前,皮質醇與睾酮(cortisol / testosterone, C/T)的比值於運動訓練中被視為一個重要的生物指標 (biomarker),其C/T值可反映運動員是否處於過度訓練狀態或壓力下。另一方面,過去的研究結果發現,乳酸(lactate, LA) 於離體 (in vitro) 及活體 (in vivo) 實驗中,可經由cAMP路徑刺激內生性的睪酮增加。另一方面,過去的研究也發現,皮質酮 (corticosterone, CORT) 也會藉由影響cAMP路徑減少萊氏細胞 (Leydig cells) 分泌睪酮能力。以往的研究內容分別著重於皮質酮或乳酸對於萊氏細胞產生睪酮的訊息路徑探討。目前,對於共同處理皮質酮與乳酸影響萊氏細胞睪酮生合成 (steroidogenesis) 及其相關訊息傳遞路徑蛋白表現目前尚不清楚,仍需進一步的研究。因此,本實驗欲模擬過度運動訓練當中產生之皮質酮及乳酸的交互作用下,探討對於萊氏細胞產生睪酮的機轉。本實驗以大鼠睾丸萊氏細胞做為實驗對象,並同時投予乳酸 (0、2.5、5、10 和 20 mM)、皮質酮(10-9~10-4 M)、8-bromo-adenosine-3':5'-cyclic monophosphate (8-Br-cAMP, cAMP類似物, 10-4 M)、forskolin (FSK, adenyly cyclase 活化劑, 10-5 M)、人絨毛膜促性腺激素 (hCG, 0.05 IU/ml) 或不同濃度皮質酮結合不同濃度之乳酸、8-Br-cAMP、hCG和FSK於34℃下培養60分鐘。培養液中的睪酮濃度利用放射免疫法 (radioimmunoassay, RIA) 測定。而黃體生成素受體 (luteinizing hormone receptor, LHR)、類固醇急性調節蛋白 (steroidogenic acute regulatory protein, StAR)、膽固醇側鏈分解酶 (cytochrome P450 cholesterol side-chain cleavage enzyme, P450scc) 和蛋白質激酶A (protein kinase A, PKA) 等蛋白表現則利用西方點墨法 (western blot) 進行分析。實驗結果顯示,乳酸 (10或20 mM) 促使細胞膜上的LHR蛋白被醣基化 (glycosylation) 後,增進LHR的功能效率 (functional efficiency) 及adenylyl cyclase活性,促使胞內cAMP濃度及下游P450scc的蛋白表現增加,最後導致睪酮分泌量增加。另一方面,當給予不同濃度的皮質酮培養60分鐘後,睪酮的分泌量會隨著皮質酮濃度的增加而遞減。單純處理皮質酮不影響LHR及StAR的蛋白表現及細胞內cAMP的濃度。然而,單獨處理皮質酮會減弱hCG及FSK刺激的效應,以及減少PKA及P450scc的蛋白表現,最後導致睪酮產量下降。相似的,原本萊氏細胞於乳酸培養60分鐘後提昇的LHR蛋白表現,會因為給予皮質酮導致失去原先提昇LHR蛋白表現的效果。因此,皮質酮可能會影響乳酸提升LHR蛋白的功能效率。此外,皮質酮也會抑制 (abolished) 乳酸刺激的胞內cAMP濃度。再者,皮質酮也會下調 (down-regulation) PKA與P450scc的蛋白表現,最後導致睪酮分泌量下降。本研究結果發現,乳酸會刺激萊氏細胞分泌睪酮產量增加,但會因為皮質酮的共同處理作用而被抑制。因此,本實驗的結論是,乳酸藉由LHR-cAMP-P450scc路徑增加睪酮的分泌量;然而,皮質酮除了影響乳酸提升LHR蛋白的功能效率 (functional efficiency) 外,還減少cAMP的生成 (generation),下調PKA及P450scc的蛋白表現,最後導致萊氏細胞分泌睪酮的產量減少。
It has been well known that the increased level of testosterone not only contributes to skeletal muscle hypertrophy but also enhances exercise performance after training or during competition in elite athletes. Previous studies reported that hyper-glucocorticoid levels diminished androgen production during overtraining trail and stress. Thus, the cortisol to testosterone (C/T) ratio was regarded as a powerful candidate biomarker presented the trainer under overtraining condition or stress. Previous studies have indicated that treatment of lactate stimulated testosterone release by cAMP pathway. Other studies also evidenced that corticosterone decreased testosterone level by cAMP in Leydig cells. The previous studies are focused on effects of corticosterone or lactate on testosterone synthesis in Leydig cells. However, interactive effects of corticosterone combined with lactate on testosterone production and underlying mechanisms in Leydig cells still remain unclear. Therefore, the aim of the present study was to investigate the interactive effects of corticosterone and lactate on testosterone production and relative-mechanisms of steroidogenesis in Leydig cells. The primary Leydig cells were purified from rat testes and then treated with lactate (0, 2.5, 5, 10 and 20 mM), corticosterone (CORT, 10-9 ~ 10-4 M), 8-bromo-adenosine-3':5'-cyclic monophosphate (8-Br-cAMP, 10-4 M), forskolin (FSK, an adenylyl cyclase activator, 10-5 M), human chorionic gonadotropin (hCG, 0.05 IU/ml) or different concentrations of CORT plus different concentrations of lactate, 8-Br-cAMP, hCG and FSK at 34℃ for 60 min. The concentrations of testosterone in medium were measured by radioimmunoassay. The protein expressions of luteinizing hormone receptor (LHR), protein kinase A (PKA), steroidogenic acute regulatory protein (StAR) and cytochrome P450 cholesterol side-chain cleavage enzyme (P450scc) were analyzed by western blot. The results showed that treatment of lactate (10 and 20 mM) significantly increased testosterone production by improving adenylyl cyclase activity and intracellular cAMP level. Furthermore, lactate significantly increased protein expressions of LHR and P450scc. On the other side, treatment of CORT alone for 60 min resulted in a dose-dependent reduction of testosterone release in vitro. Moreover, CORT alone did not affect intracellular cAMP generation, but significantly attenuated hCG- and FSK-elevated testosterone production in Leydig cells. In addition, challenge of CORT did not change protein expressions of PKA and P450scc as compared with vehicle. Similarly, the enhanced protein expression of LHR by lactate was abolished following the treatment with CORT plus lactate. CORT down regulated the protein expressions of PKA and P450scc. Besides, CORT also abolished lactate-stimulated intracellular cAMP levels. Therefore, we found that lactate-elevated testosterone levels can be inhibited by co-treatment with CORT. The novel findings conclude that (1) lactate stimulated testosterone production by enhancing cAMP activity and increasing protein expressions of LHR and P450scc, and (2) inhibitory effects of CORT on lactate-stimulated testosterone production were at least in part due to the downregulation of PKA and P450scc protein expressions, as well as cAMP activity in isolated rat Leydig cells.
致謝 i
目錄 ii
圖錄 iv
重要名詞中英文對照表 v
中文摘要 vi
英文摘要 (Abstract) viii
第一章、文獻回顧 1
一、睪丸組織結構、功能與細胞型態 1
二、睪酮的生合成過程及其生理功能 1
三、運動訓練對睪酮濃度的影響 3
四、糖皮質素的生合成及其生理功能 4
五、糖皮質素及睪酮的比值與運動表現的關係 6
六、皮質酮對萊氏細胞產生睪酮的影響 8
七、研究動機 9
第二章、材料與方法 10
一、抗體與試劑 10
二、實驗動物 10
三、萊氏細胞的製備與純化 11
四、實驗設計 11
五、細胞存活率測試 12
六、蛋白質萃取與西方墨點法 12
七、放射免疫測定法 13
八、細胞內cAMP濃度測定 14
九、去醣基化實驗 14
十、核糖核酸純化與即時聚合酶鏈鎖反應分析 15
十一、統計方法 15
第三章、實驗結果 17
一、乳酸刺激大鼠萊氏細胞分泌睪酮 17
二、乳酸對於睪酮生合成路徑相關蛋白表現的影響 17
三、乳酸對於萊氏細胞LHR mRNA表現之影響 18
四、PNGase去除萊氏細胞受乳酸刺激,LHR去醣基後之蛋白表現 18
五、皮質酮抑制大鼠萊氏細胞睪酮分泌的效應 18
六、皮質酮下調PKAα和P450scc 蛋白表現進而減少睪酮分泌量 19
七、皮質酮不影響萊氏細胞GR及MR的蛋白表現 19
八、皮質酮減弱乳酸誘發的睪酮分泌量 20
九、皮質酮減弱乳酸誘發的PKAα和P450scc蛋白表現 20
十、皮質酮抑制乳酸刺激萊氏細胞內的cAMP濃度 21
第四章、討 論 22
圖表與圖註 27
參考文獻 40
附錄 46

圖錄
圖一、萊氏細胞中睪酮生合成之相關機制圖 27
圖二、乳酸對大鼠萊氏細胞分泌睪酮之影響 28
圖三、乳酸對於大鼠萊氏細胞中LHR、PKA、StAR及P450scc蛋白之影響 29
圖四、乳酸對於萊氏細胞LHR mRNA表現之影響 30
圖五、觀察PNGase去除萊氏細胞受乳酸刺激,LHR去醣基後之蛋白表現 31
圖六、皮質酮對大鼠萊氏細胞分泌睪酮及其細胞生存率之影響 33
圖七、皮質酮對於大鼠萊氏細胞中LHR、PKA、StAR及P450scc蛋白之影響 34
圖八、不同濃度皮質酮對於大鼠萊氏細胞GR及MR蛋白之影響 35
圖九、不同濃度之皮質酮結合不同濃度的乳酸,對大鼠萊氏細胞分泌睪酮之影響 36
圖十、共同處理皮質酮與乳酸對於大鼠萊氏細胞中LHR、PKA、StAR及P450scc蛋白之影響 37
圖十一、皮質酮、乳酸或共同處理糖皮質素與乳酸對於大鼠萊氏細胞中cAMP濃度之影響 38
圖十二、皮質酮抑制乳酸刺激睪酮生合成之示意圖 39
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