Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Liver Transpl. 2009 Nov;15(11):1613-21. doi: 10.1002/lt.21879.
The nuclear factor-kappaB inhibitory protein A20 demonstrates hepatoprotective abilities through combined antiapoptotic, anti-inflammatory, and pro-proliferative functions. Accordingly, overexpression of A20 in the liver protects mice from toxic hepatitis and lethal radical hepatectomy, whereas A20 knockout mice die prematurely from unfettered liver inflammation. The effect of A20 on oxidative liver damage, as seen in ischemia/reperfusion injury (IRI), is unknown. In this work, we evaluated the effects of A20 upon IRI using a mouse model of total hepatic ischemia. Hepatic overexpression of A20 was achieved by recombinant adenovirus (rAd.)-mediated gene transfer. Although only 10%-25% of control mice injected with saline or the control rAd.beta galactosidase survived IRI, the survival rate reached 67% in mice treated with rAd.A20. This significant survival advantage in rAd.A20-treated mice was associated with improved liver function, pathology, and repair potential. A20-treated mice had significantly lower bilirubin and aminotransferase levels, decreased hemorrhagic necrosis and steatosis, and increased hepatocyte proliferation. A20 protected against liver IRI by increasing hepatic expression of peroxisome proliferator-activated receptor alpha (PPARalpha), a regulator of lipid homeostasis and of oxidative damage. A20-mediated protection of hepatocytes from hypoxia/reoxygenation and H(2)O(2)-mediated necrosis was reverted by pretreatment with the PPARalpha inhibitor MK886. In conclusion, we demonstrate that PPARalpha is a novel target for A20 in hepatocytes, underscoring its novel protective effect against oxidative necrosis. By combining hepatocyte protection from necrosis and promotion of proliferation, A20-based therapies are well-poised to protect livers from IRI, especially in the context of small-for-size and steatotic liver grafts. Liver Transpl 15:1613-1621, 2009. (c) 2009 AASLD.
核因子-κB 抑制蛋白 A20 通过联合抗凋亡、抗炎和促增殖功能发挥肝保护作用。因此，肝脏中 A20 的过表达可保护小鼠免受毒性肝炎和致命性自由基肝切除术的影响，而 A20 敲除小鼠则因不受控制的肝炎症而过早死亡。A20 对氧化肝损伤（如缺血/再灌注损伤 [IRI]）的影响尚不清楚。在这项工作中，我们使用全肝缺血的小鼠模型评估了 A20 对 IRI 的影响。通过重组腺病毒（rAd.）介导的基因转移实现肝内 A20 的过表达。尽管仅注射生理盐水或对照 rAd.β半乳糖苷酶的对照组中有 10%-25%的小鼠在 IRI 中存活，但 rAd.A20 治疗的小鼠的存活率达到 67%。rAd.A20 治疗的小鼠具有显著的生存优势，与改善的肝功能、病理学和修复潜能相关。A20 治疗的小鼠胆红素和转氨酶水平显着降低，出血性坏死和脂肪变性减少，肝细胞增殖增加。A20 通过增加过氧化物酶体增殖物激活受体 α（PPARα）的肝表达来保护肝脏免受 IRI，PPARα 是脂质稳态和氧化损伤的调节剂。A20 预处理可逆转 PPARα 抑制剂 MK886 对肝细胞缺氧/再氧合和 H2O2 介导的坏死的保护作用。总之，我们证明 PPARα 是 A20 在肝细胞中的一种新靶点，强调了其对氧化坏死的新型保护作用。通过结合肝细胞对坏死的保护和增殖的促进，基于 A20 的治疗方法有望保护肝脏免受 IRI，特别是在小体积和脂肪性肝移植物的情况下。肝脏移植 15:1613-1621,2009。（c）2009 AASLD。
