藥理研究：奧曲肽的肝臟保護作用

研究對象：大鼠

分析檢測平臺：GC-TOF／MS（BIOTREE）

期刊：Liver international

影響因子：4.85

發(fā)表時間：2015

摘要：

Background & Aims: Insufficient liver regeneration and hepatocyte injury caused by excessive portal perfusion are considered to be responsible for post-hepatectomy liver failure (PLF) or small-for-size syndrome in living- donor liver transplantation. Somatostatin can decrease portal vein pressure (PVP) but simultaneously inhibits liver regeneration. This interesting para- dox motivated us to investigate the outcome of PLF in response to somatostatin treatment. Methods: Rats receiving extended partial hepatectomy (90% PH) were treated with octreotide, a somatostatin analogue, or placebo. Animal survival, serum parameters and hepatic histology were evaluated. Metabolomic analysis was performed to investigate the effect of octreotide on hepatocyte metabolism. Results: Despite significantly inhibiting early regeneration, octreotide application noticeably improved the hepatic histology, liver function and survival after PH but did not decrease the PVP level. Metabolomic analysis exhibited that octreotide profoundly and exclusively altered the levels of five metabolites that participate in or closely associate with the methionine cycle, a biochemical reaction that uniquely produces S-adenosylmethionine (SAMe), an active methyl residual donor for methyl- transferase reactions. Among these metabolites, methylthioadenosine (MTA), a derivate of SAMe, increased three-fold and was found independently improve the hepatic histology and reduce inflammatory cytokines in hepatectomized rats. Conclusions: Octreotide exclusively regulates the methionine cycle reaction and augments the MTA level in hepatocytes. MTA prominently protects hepatocytes against shear stress injury and reduces the secondary inflammation, thereby protecting rats from PLF.

Keywords: hepatectomy liver failure (PLF)、portal vein pressure (PVP)、methylthioadenosine (MTA)

一、研究背景：

肝臟在部分切除后仍可通過激活成熟肝細胞進行自我修復，這一特點是肝臟切除術及肝臟活體移植（living-donor liver transplantation， LDLT）技術的重要基礎。然而在治療復雜肝臟疾病時，采用肝臟切除術后常發(fā)現(xiàn)術后肝功能失常（post-hepatectomy liver failure, PLF），且肝臟移植后常出現(xiàn)小體積綜合癥（small-for-size syndrome, SFSS），導致術后死亡率升高。

門靜脈過度灌注是PLF的重要征兆，同時門靜脈血壓和剪切力升高也可直接導致SFSS。因此降低門靜脈血壓可作為預防SFSS和PLF的一種有效策略。奧曲肽是一種生長抑素，具有降低PVP作用，臨床常用于治療肝硬化引起的上消化道出血。雖然有報道稱奧曲肽可降低SFSS發(fā)生率，但其機制尚不明確。同時，作為生長抑素，該藥品是否會因抑制肝臟細胞再生而導致PLF尚不確定。為嘗試回答這些問題，本文嘗試在大鼠肝切除術模型中研究奧曲肽的作用效果和機制。

二、方法流程：

三、研究結果與討論：

1、奧曲肽使用后大鼠的生物學功能變化：

1）奧曲肽抑制肝細胞早期增殖

2）奧曲肽并未降低門靜脈血壓（PVP）

3）使用奧曲肽后大鼠存活率和肝功能數(shù)據(jù)顯著高于對照

圖1奧曲肽使用后大鼠的生物學功能變化 

2、奧曲肽引起的肝臟代謝組變化

1）主成分分析（PCA）表明奧曲肽組的代謝物出現(xiàn)整體變化；

2）使用偏最小二乘回歸判別分析（PLS-DA）篩選標志性差異物；

3）結合標志型差異物發(fā)現(xiàn)奧曲肽作用途徑：蛋氨酸循環(huán)

4）蛋氨酸循環(huán)中的甲硫腺苷（MTA）可能提高術后肝功能并降低系統(tǒng)性炎癥發(fā)生

圖2 多元變量統(tǒng)計分析建立PCA和PLS-DA模型的得分圖

3、多元變量統(tǒng)計分析建立PCA和PLS-DA模型的得分圖：

1） 表型特點：雖然抑制早期肝臟細胞自修復，但仍可有效提高術后肝功能

2） 奧曲肽的肝臟保護作用與其降低門靜脈血壓作用無關

3） 通過代謝組學分析，發(fā)現(xiàn)奧曲肽作用的關鍵因素：細胞內(nèi)MTA水平的升高

4） 機制探索: MTA通過抑制炎癥反應促進肝細胞再生

圖3 使用MTA后大鼠的生物學功能變化

四、亮點和展望

奧曲肽雖然抑制了早期肝細胞再生，但仍表現(xiàn)出顯著的肝臟保護作用

該護肝效果與奧曲肽已知的降低門靜脈血壓作用并無明顯關系

通過代謝組學研究分析發(fā)現(xiàn)奧曲肽引起新的肝臟保護物質—MTA的上升

通過給藥實驗進一步證明MTA在肝臟切除模型中具有明顯的護肝作用

展望:奧曲肽提高蛋氨酸途徑和MTA水平的詳細機制還需進一步研究

展望:可通過靶標代謝組學方法對MTA及蛋氨酸途徑物質進行精確定量研究，并對可能的臨床應用進行考察

閱讀文獻下載地址：

Zhenggui et al., Octreotide prevents liver failure through upregulating 5'-methylthioadenosine in extended hepatectomized rats. Liver International. (2016). 36(2): 212–222