Apobec-1 Complementation Factor Modulates Liver Regeneration by Post-transcriptional Regulation of Interleukin-6 mRNA Stability
Apobec-1 Complementation Factor Modulates Liver Regeneration by Post-transcriptional Regulation of Interleukin-6 mRNA Stability
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DOI：
10.1074/jbc.m110.115147
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发表时间：
2010-06-18
影响因子：
4.8
通讯作者：
Davidson, Nicholas O.
中科院分区：
文献类型：
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作者：
Blanc, Valerie;Sessa, Kimberly J.;Davidson, Nicholas O.
Apobec-1 互补因子 (ACF) 是核心复合物的 RNA 结合亚基，介导载脂蛋白 B (apoB) mRNA 的 C 到 U RNA 编辑。小鼠Acf基因的靶向缺失会导致早期胚胎死亡，并且Acf(-/-)囊胚无法植入和增殖，这表明ACF在细胞生长和分化中发挥着关键作用。在这里，我们证明杂合 Acf(+/-) 小鼠在部分肝切除术 (PH) 后表现出增殖减少和肝脏质量恢复受损。为了探究肝脏再生受损的机制，我们检测了白细胞介素 6 (IL-6) 的激活，白细胞介素 6 是 PH 后诱导肝细胞增殖所需的关键细胞因子。在杂合 Acf(+/-) 小鼠中，PH 后肝脏 IL-6 mRNA 丰度的峰值诱导减弱 >80%，同时血清 IL-6 水平降低。与杂合 Acf(+/-) 小鼠相比，野生型小鼠分离的 Kupffer 细胞 (KC) 的 IL-6 分泌量高出 2 倍。重组ACF以高亲和力结合IL-6 3'非翻译区中的富含AU的区域，并且与野生型对照相比，从Acf(+/-)小鼠分离的KC中IL-6 mRNA半衰期显着缩短。这些发现表明，ACF 至少部分通过控制 IL-6 mRNA 的稳定性来调节 PH 后的肝再生。结果进一步表明，除了 apoB RNA 编辑之外，ACF 还具有新的 RNA 靶点和意想不到的生理功能。
Apobec-1 complementation factor (ACF) is the RNA binding subunit of a core complex that mediates C to U RNA editing of apolipoprotein B (apoB) mRNA. Targeted deletion of the murine Acf gene is early embryonic lethal and Acf(-/-) blastocysts fail to implant and proliferate, suggesting that ACF plays a key role in cell growth and differentiation. Here we demonstrate that heterozygous Acf(+/-) mice exhibit decreased proliferation and impaired liver mass restitution following partial hepatectomy (PH). To pursue the mechanism of impaired liver regeneration we examined activation of interleukin-6 (IL-6) a key cytokine required for induction of hepatocyte proliferation following PH. Peak induction of hepatic IL-6 mRNA abundance post PH was attenuated >80% in heterozygous Acf(+/-) mice, along with decreased serum IL-6 levels. IL-6 secretion from isolated Kupffer cells (KC) was 2-fold greater in wild-type compared with heterozygous Acf(+/-) mice. Recombinant ACF bound an AU-rich region in the IL-6 3'-untranslated region with high affinity and IL-6 mRNA half-life was significantly shorter in KC isolated from Acf(+/-) mice compared with wild-type controls. These findings suggest that ACF regulates liver regeneration following PH at least in part by controlling the stability of IL-6 mRNA. The results further suggest a new RNA target and an unanticipated physiological function for ACF beyond apoB RNA editing.