多菌性敗血症中肝臟Retinoid X Receptor Alpha基因抑制機轉之探討

The Mechanism of Hepatic Retinoid X Receptor Alpha Suppression during Polymicrobial Sepsis

蔡麗燕(Li-Yen Tsai)

指導教授 ： 許勤

高雄醫學大學/醫學院/生理及分子醫學研究所/碩士(2007年)

https://doi.org/10.6832/KMU.2007.00044

摘要

Retinoid X receptor α (RXRα) 與其他胞核受體共同作用於調節膽酸相關之運送蛋白或其代謝酵素之基因表現，如rat bile acid CoA: amino acid N- acyltransferase (rBAT) 等。根據我們實驗室先前的活體研究結果顯示，以盲腸結紮穿孔術 (cecal ligation and puncture；CLP) 引發Sprague-Dawley大白鼠敗血症之動物模式中，發現肝臟RXRα於細胞核蛋白質表現量減少是抑制rBAT基因表達的重要因子之ㄧ。然而，在多菌性敗血症中抑制RXRα表現量之分子機轉至今尚未清楚。過去文獻指出在內毒素的刺激下造成RXRα mRNA明顯下降，其中mRNA之降解可能扮演重要的角色。調控mRNA降解的RNA 結合蛋白 (RNA binding proteins)，如TTP、AUF-1、KSRP及HuR、PCBP1分別促進與抑制mRNA之降解。因此，我們假設在敗血症病程中HuR、PCBP1及TTP、AUF-1、KSRP參與RXRα mRNA的降解進而影響rBAT之基因表達。根據實驗結果顯示，RXRα mRNA表現量顯著減少 (CLP後3、6小時) 發生於rBAT受抑制之前，且RXRα mRNA減少之百分比 (74%) 遠大於蛋白質受抑制之程度 (39%)。除此之外，亦發現敗血症病程中，肝臟細胞質KSRP與RXRα 3’-UTR結合能力的上升伴隨著RXRα mRNA降解增加。根據結果推論KSRP與RXRα 3’-UTR之結合可能促進RXRα mRNA降解，進而抑制rBAT基因之表達。

關鍵字

多菌性敗血症 ； RXRα

並列摘要

Retinoid X receptor alpha (RXRα) is involved in the regulation of bile acid related transporters and metabolic enzymes, such as rat bile acid CoA: amino acid N-acyltransferase (rBAT). Our previous in-vivo study found that the decrease of nuclear RXRα caused the suppression of rBAT in the rat liver of septic model induced by cecal ligation and puncture (CLP). However, the molecular mechanisms of RXRα down-regulation during polymicrobial sepsis have not been clarified. Recent study indicated that the decrease of RXRα mRNA level is primarily due to a LPS-induced specific degradation of RXRα mRNA. The degradation of mRNA is regulated by RNA binding proteins, such as Hu antigen R (HuR), poly-C binding protein and tristetraprolin (TTP), A-U rich binding protein 1 (AUF-1), K homology-type splicing regulatory protein (KSRP), which stabilize and destabilize mRNA, respectively. Therefore, we hypothesize that HuR, PCBP1 and/or TTP, AUF-1, KSRP participates in the RXRα mRNA degradation during polymicrobial sepsis. The results showed that significantly decrease of RXRα mRNA level occurred before rBAT suppression. The decrease of RXRα mRNA (74%) was significantly more prominent than that of protein level (39%). In addition, the increase of KSRP binding to RXRα 3’-UTR associated with shortened the poly-A tail of RXRα mRNA was observed in septic liver. These results indicate that increase of KSRP binding to RXRα 3’-UTR may contribute to the enhancement of RXRα mRNA degradation, which leads to rBAT suppression during sepsis.

並列關鍵字

polymicrobial sepsis ； RXRα

參考文獻

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