醛糖还原酶在脂肪肝脏再生中的作用及其机制

Fatty liver is the most common hepatic disorder in humans, which can be caused by a variety of aetiologies such as obesity, diabetes and alcohol consumption. Fatty liver is associated with more frequent occurrence of graft dysfunction and liver failure after liver transplantation and liver resection duo to increased susceptibility to ischemia-reperfusion injury (IRI) and impaired liver regeneration. Our previous study showed that aldose reductase (AR) promoted fatty liver IRI through regulating oxidative stress, cell apoptosis and inflammatory response. Our preliminary results showed that the expression of AR was increased in liver after liver transplantation and liver resection, especially in fatty liver group. Over-expressed of AR was associated with impaired liver regeneration in fatty liver. Furthermore, AR was also up-regulated in human hepatocyte cell line LO2 underwent fatty change and in vitro IRI. The knockout of AR significantly increased the ability of anti-oxidative stress and promoted fatty liver regeneration after liver resection. These data suggest that AR may play important roles in fatty liver regeneration. In this project, we aim to investigate the roles of AR in fatty liver regeneration and to explore the underlying mechanisms through in vivo and in vitro studies. Our results will be important not only for understanding the roles and molecular mechanisms of AR in fatty liver regeneration but also for developing a new therapeutic strategy to reduce the fatty liver IRI and promote fatty liver regeneration.

脂肪肝人群比率日益升高，此类患者经历肝切除手术或作为移植供肝时，对肝缺血再灌注损伤（IRI）更敏感,且术后肝再生能力减弱及受损，增加术后肝功能衰竭和肝移植物无功能的风险。我们已完成的研究显示醛糖还原酶（AR）通过调节肝脏氧化应激损伤、细胞凋亡及炎症反应促进了脂肪肝的IRI。前期动物实验表明，脂肪肝供肝移植及脂肪肝切除术后AR表达明显高于正常肝组，且术后肝再生能力弱于正常组。人肝细胞系LO2在脂肪变性及模拟IRI后AR表达也异常升高。敲除小鼠AR基因提高了肝脏抗氧化应激能力，增加ATP合成, 促进脂肪肝术后的修复和再生。因此我们推测AR可能在脂肪肝脏再生中起着重要的作用。本课题选用AR基因敲除小鼠，将动物实验与体外实验相结合，从分子、细胞和动物水平探讨AR在脂肪肝脏再生中的作用及其机制。并进一步寻求合适的干预手段，为临床治疗肝脏IRI及加快术后肝脏再生，提供新的实验基础和理论依据。

脂肪肝人群比率日益升高，此类患者经历肝切除手术或作为移植供肝时，对肝缺血再灌注损伤（IRI）更敏感,且术后肝再生能力减弱及受损，增加术后肝功能衰竭和肝移植物无功能的风险。我们已完成的研究显示醛糖还原酶（AR）通过调节肝脏氧化应激损伤、细胞凋亡及炎症反应促进了脂肪肝的IRI。而AR在脂肪肝脏再生及非酒精性脂肪性肝炎(NASH)中的作用及机制尚不清楚。本课题选用AR基因敲除小鼠探讨AR在肝再生和NASH的作用及机制。结果表明：肝移植和肝切除术后，脂肪肝组肝再生延迟，而手术后AR表达显著增高，在脂肪肝组尤为明显。敲除AR基因可缓解肝切除后肝脏损伤，提高肝脏与体重比例，加速肝再生。敲除AR基因提高了细胞周期相关基因CyclinA2/B/D1/E1的表达，提高了组织ATP的含量和PPAR-α、PPAR-γ、SDHB、AMPK-α、SIRT1、PGC1-α基因的表达，促进线粒体生物合成和能量代谢促进肝再生。高脂饮食后AR表达明显升高。敲除AR基因有效降低高脂饮食诱导的肝脏损伤，肝脏/体重比和NASH。敲除AR基因提高了高脂饮食后PPARα/γ, Adiponectin，PGC1α的表达，促进肝脏脂质代谢。敲除AR有效降低高脂饮食诱导的炎症反应，减少巨噬细胞和中性粒细胞浸润和TNFα、MCP-1、iNOS、CCL3、CXCL2、CXCL5、CXCL10、ICAM1、VCAM1基因的表达。敲除AR增强了细胞自噬及相关蛋白如ULK1、ATG5、 Beclin-1的表达以缓解NASH。这些结果表明，AR在肝再生和NASH中起着重要的作用，敲除AR可加速肝脏再生和缓解NASH，为临床治疗NASH及加快术后肝脏再生提供了潜在靶点。