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標題: 骨髓間質幹細胞治療由Akr1A1基因缺失所誘發酒精性肝損傷之功效評估
Evaluation of the therapeutic efficacy of bone marrow mesenchymal stem cells on alcoholic liver injury triggered by aldo-keto reductase 1A1 (Akr1A1) gene deficiency
作者: 陳婉如
Wan-Ru Chen
關鍵字: 醛還原酶;骨髓間質幹細胞;酒精;肝損傷;AKR1A1;Bone marrow mesenchymal stem cell;alcohol;liver injury
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酒精性肝損傷起因於飲酒,長期大量飲酒容易形成酒精性脂肪肝、肝炎、肝纖維化甚至發展成不可逆的肝硬化,成為全球慢性肝病的主要致病因素,而酒精性肝損傷病程發展取決於酒精攝取量、持續時間、飲食以及個體遺傳變異性。AKR1A1屬於醛酮還原家族成員,由醛還原酶基因所編碼,是機體依賴NADPH的重要酵素,能將多種醛類還原成其相對應醇類物質,並參與細胞的解毒作用。當體內先天缺乏醛還原酶,等同於瓦解細胞抵抗毒害物質的能力,進而造成細胞毒性,AKR1A1作為體內醛還原解毒酵素,對於酒精引起肝臟疾病之關聯性仍待探究。因此本試驗第一部分將同時建立AKR1A1缺乏小鼠及其遺傳背景ICR小鼠酒精誘導肝損傷模式,探討AKR1A1缺乏對酒精性肝損傷之易感性。試驗中使用9週齡ICR及AKR1A1eGFP/eGFP小鼠,利用Lieber-Decarli流質飲食模式,分別餵食1-4 %酒精液態飼料及正常液態飼料使其適應一週,小鼠至10週齡即以5 %酒精濃度餵養,進行為期八週的實驗。結果顯示,酒精造成Akr1A1eGFP/eGFP小鼠出現肝功能異常、肝臟三酸甘油脂蓄積及肝細胞脂肪變性,並誘發酒精代謝途徑中CYP2E1蛋白表現,導致脂質過氧化物4-HNE產生,使肝細胞釋放促炎因子TNF-α 與IL-1β,並且出現死亡現象;然而酒精並未誘發ICR小鼠明顯肝損傷,且於蛋白層次中發現酒精餵養增加ICR小鼠肝臟AKR1A1的表現,顯示醛還原酶遺傳性缺陷大幅提高小鼠對酒精之敏感性。過去研究陸續支持間質幹細胞具有修復遺傳缺陷疾病之潛力,因此試驗第二部分欲藉由骨髓間質幹細胞移植,評估移植治療是否修復醛還原酶功能並進一步改善由醛還原酶缺乏所導致肝損傷病症。首先以尾靜脈注射移植骨髓間質幹細胞,於移植四週後犧牲小鼠。由螢光顯微鏡與幹細胞表面標記染色皆可發現部分骨髓間質幹細胞分布於肝臟,經IHC染色結果顯示細胞移植後Akr1A1eGFP/eGFP小鼠肝臟表現醛還原酶,接著觀察肝損傷修復情形,藉由蛋白層次證實骨髓間質幹細胞釋出旁分泌因子TGFβ、HGF參與肝細胞修復,且降低肝臟三酸甘油脂堆積、脂肪變性並回復肝功能,更提升抗氧化物質GSH含量並削弱CYP2E1代謝途徑,減少脂質過氧化產物MDA、4-HNE的生成,降低過氧化物質對肝臟的損害,有效抑制發炎反應,顯示醛還原酶的存在可提高小鼠對酒精性肝損傷的易感性。綜合上述結果,本試驗證實醛還原酶在酒精性肝損傷之重要性,有潛力作為研究酒精代謝疾病的動物模式。

Alcoholic liver disease (ALD) is caused by excessive alcohol consumption. The spectrum of alcohol-related liver injury varies from hepatic steatosis, steatohepatitis, alcoholic fibrosis to irreversible cirrhosis. Alcohol is emerging as the commonest cause of chronic liver disease worldwide. The severity and prognosis of alcohol-induced liver disease depends on the amount, duration of alcohol consumption, diet as well as genetic predisposition of an individual. AKR1A1 is a member of the aldo-keto reductase (AKR) superfamily, which is encoded by the AKR1A1 gene. The enzyme catalyze the reduction of various aldehydes to their corresponding alcohols in an NADPH-dependent manner and participate in the detoxification. Aldehyde reductase deficiency contribute to cell damage because of toxic substances stimulation AKR1A1 acts as an aldehyde-reducing and detoxifying enzyme in organism, the association of alcohol-induced liver disease remains to be explored. In this study, the first aim of the experiment will establish the model of alcohol-induced liver injury in AKR1A1 deficient mice and their genetic background ICR mice, revealing the susceptibility of AKR1A1 deficiency to alcoholic liver injury. The 9-week-old ICR and AKR1A1eGFP/eGFP mice were divided into four groups that was used to fed Lieber-Decarli diet containing 1-4% alcohol liquid diet or an isocaloric (Pair-fed) control diet adjusted by 1 weeks. The mice were fed 5 % alcohol for 8 weeks at 10-week-old. The results showed that alcohol caused abnormal liver function, hepatic triglyceride accumulation and steatosis in AKR1A1eGFP/eGFP mice. Alcohol consumption increases the CYP2E1 levels, leading to lipid peroxidation and lipid peroxidation products such as 4-hydroxynonenal , increasing pro-inflammatory cytokines TNF-α and IL-1β protein level and the risk of death. Interestingly, Alcohol did not cause liver injury significant in ICR mice. However, alcohol feeding increased hepatic AKR1A1 protein level. It shows that the genetic defect of aldehyde reductase susceptibility to alcohol. Over the years, growing number of studies have provided evidence in support the potential of mesenchymal stem cells to fixing genetic disorders. Therefore, the second aim of the experiment is to evaluate whether aldehyde reductase function repaired by bone marrow mesenchymal stem cells after cell transplantation to further improve liver injuury caused by aldehyde reductase deficiency. First, Bone marrow mesenchymal stem cells were transplanted by tail vein injection, and the mice were sacrificed four weeks after transplantation. Some mesenchymal stem cells were found in the liver by fluorescence microscopy and stem cell surface marker staining. IHC staining showed that the liver of AKR1A1eGFP/eGFP mice ecpressed aldehyde reductase after cell transplantation. Then observe the repair of liver damage, Hierarchy confirmed that mesenchymal stem cells release paracrine factors TGFβ and HGF involved in hepatocyte repair, and reduce hepatic triglyceride accumulation, steatosis and restore liver function, enhance antioxidant GSH content and decreased CYP2E1 protein levels, reduce lipid peroxidation products MDA, 4-HNE damage liver and effectively decreases the inflammation. It was shown that aldehyde reductase increases the susceptibility of mice to alcoholic liver injury. In conclusion, we confirmed the importance of aldehyde reductase in alcoholic liver injury and has potential as an animal model for studying alcohol related diseases.
Rights: 同意授權瀏覽/列印電子全文服務,2022-02-12起公開。
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