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首页> 美国卫生研究院文献>Cell Death and Differentiation >Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration
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Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration

机译：A20杂合基因敲除小鼠肝脏切除后的致命杀伤力揭示了A20在肝脏再生中的关键作用

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Hepatic expression of A20, including in hepatocytes, increases in response to injury, inflammation and resection. This increase likely serves a hepatoprotective purpose. The characteristic unfettered liver inflammation and necrosis in A20 knockout mice established physiologic upregulation of A20 as integral to the anti-inflammatory and anti-apoptotic armamentarium of hepatocytes. However, the implication of physiologic upregulation of A20 in modulating hepatocytes' proliferative responses following liver resection remains controversial. To resolve the impact of A20 on hepatocyte proliferation and the liver's regenerative capacity, we examined whether decreased A20 expression, as in A20 heterozygous knockout mice, affects outcome following two-third partial hepatectomy. A20 heterozygous mice do not demonstrate a striking liver phenotype, indicating that their A20 expression levels are still sufficient to contain inflammation and cell death at baseline. However, usually benign partial hepatectomy provoked a staggering lethality (>40%) in these mice, uncovering an unsuspected phenotype. Heightened lethality in A20 heterozygous mice following partial hepatectomy resulted from impaired hepatocyte proliferation due to heightened levels of cyclin-dependent kinase inhibitor, p21, and deficient upregulation of cyclins D1, E and A, in the context of worsened liver steatosis. A20 heterozygous knockout minimally affected baseline liver transcriptome, mostly circadian rhythm genes. Nevertheless, this caused differential expression of >1000 genes post hepatectomy, hindering lipid metabolism, bile acid biosynthesis, insulin signaling and cell cycle, all critical cellular processes for liver regeneration. These results demonstrate that mere reduction of A20 levels causes worse outcome post hepatectomy than full knockout of bona fide liver pro-regenerative players such as IL-6, clearly ascertaining A20's primordial role in enabling liver regeneration. Clinical implications of these data are of utmost importance as they caution safety of extensive hepatectomy for donation or tumor in carriers of A20/TNFAIP3 single nucleotide polymorphisms alleles that decrease A20 expression or function, and prompt the development of A20-based liver pro-regenerative therapies.
机译：响应于损伤，炎症和切除，A20的肝表达，包括在肝细胞中的表达增加。这种增加可能起到保护肝的作用。 A20基因敲除小鼠的特征性不受约束的肝脏炎症和坏死建立了A20的生理上调，这是肝细胞抗炎和抗凋亡武器库不可或缺的部分。但是，在肝切除后调节肝细胞的增殖反应中A20生理上调的含义仍存在争议。为了解决A20对肝细胞增殖和肝脏再生能力的影响，我们检查了A20杂合敲除小鼠中A20表达的降低是否会影响三分之二的部分肝切除术后的预后。 A20杂合小鼠没有表现出惊人的肝表型，表明它们的A20表达水平仍足以在基线抑制炎症和细胞死亡。但是，通常良性肝部分切除术在这些小鼠中引起了惊人的致死率（> 40％），发现了未曾怀疑的表型。在部分肝切除后，A20杂合小鼠的致死率升高是由于肝细胞增生，这是由于细胞周期蛋白依赖性激酶抑制剂p21的水平升高，以及在肝脂肪变性恶化的情况下，细胞周期蛋白D1，E和A的上调不足所致。 A20杂合基因敲除对基线肝脏转录组的影响最小，主要是昼夜节律基因。然而，这导致肝切除术后＞ 1000个基因的差异表达，阻碍脂质代谢，胆汁酸的生物合成，胰岛素信号传导和细胞周期，这是肝脏再生的所有关键细胞过程。这些结果表明，与完全敲除真正的肝脏促再生因子如IL-6相比，仅肝A20含量降低所导致的肝切除术后预后更差，从而清楚地确定了A20在促进肝脏再生中的原始作用。这些数据的临床意义极为重要，因为它们提醒广泛的肝切除术对于降低A20表达或功能的A20 / TNFAIP3单核苷酸多态性等位基因携带者的捐赠或肿瘤的安全性，并促进基于A20的肝脏促再生疗法的发展。 。

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