藥物代謝組學(xué)案例分析：奧曲肽的肝臟保護(hù)作用

藥理研究：奧曲肽的肝臟保護(hù)作用

研究對(duì)象：大鼠

分析檢測(cè)平臺(tái)：GC-TOF／MS（BIOTREE）

期刊：Liver international

影響因子：4.85

發(fā)表時(shí)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(guò)激活成熟肝細(xì)胞進(jìn)行自我修復(fù)，這一特點(diǎn)是肝臟切除術(shù)及肝臟活體移植（living-donor liver transplantation， LDLT）技術(shù)的重要基礎(chǔ)。然而在治療復(fù)雜肝臟疾病時(shí)，采用肝臟切除術(shù)后常發(fā)現(xiàn)術(shù)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(dǎo)致術(shù)后死亡率升高。

門靜脈過(guò)度灌注是PLF的重要征兆，同時(shí)門靜脈血壓和剪切力升高也可直接導(dǎo)致SFSS。因此降低門靜脈血壓可作為預(yù)防SFSS和PLF的一種有效策略。奧曲肽是一種生長(zhǎng)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(bào)道稱奧曲肽可降低SFSS發(fā)生率，但其機(jī)制尚不明確。同時(shí)，作為生長(zhǎng)抑素，該藥品是否會(huì)因抑制肝臟細(xì)胞再生而導(dǎo)致PLF尚不確定。為嘗試回答這些問(wèn)題，本文嘗試在大鼠肝切除術(shù)模型中研究奧曲肽的作用效果和機(jī)制。

二、方法流程：

三、研究結(jié)果與討論：

1、奧曲肽使用后大鼠的生物學(xué)功能變化：

1）奧曲肽抑制肝細(xì)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(duì)照

圖1奧曲肽使用后大鼠的生物學(xué)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(biāo)志性差異物；

3）結(jié)合標(biāo)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(shù)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(jì)分析建立PCA和PLS-DA模型的得分圖

3、多元變量統(tǒng)計(jì)分析建立PCA和PLS-DA模型的得分圖：

1） 表型特點(diǎn)：雖然抑制早期肝臟細(xì)胞自修復(fù)，但仍可有效提高術(shù)后肝功能

2） 奧曲肽的肝臟保護(hù)作用與其降低門靜脈血壓作用無(wú)關(guān)

3） 通過(guò)代謝組學(xué)分析，發(fā)現(xiàn)奧曲肽作用的關(guān)鍵因素：細(xì)胞內(nèi)MTA水平的升高

4） 機(jī)制探索: MTA通過(guò)抑制炎癥反應(yīng)促進(jìn)肝細(xì)胞再生

圖3 使用MTA后大鼠的生物學(xué)功能變化

四、亮點(diǎn)和展望

奧曲肽雖然抑制了早期肝細(xì)胞再生，但仍表現(xiàn)出顯著的肝臟保護(hù)作用

該護(hù)肝效果與奧曲肽已知的降低門靜脈血壓作用并無(wú)明顯關(guān)系

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

通過(guò)給藥實(shí)驗(yàn)進(jìn)一步證明MTA在肝臟切除模型中具有明顯的護(hù)肝作用

展望:奧曲肽提高蛋氨酸途徑和MTA水平的詳細(xì)機(jī)制還需進(jìn)一步研究

展望:可通過(guò)靶標(biāo)代謝組學(xué)方法對(duì)MTA及蛋氨酸途徑物質(zhì)進(jìn)行精確定量研究，并對(duì)可能的臨床應(yīng)用進(jìn)行考察

閱讀文獻(xiàn)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