Hyun Jeongeun, Choi Steve S, Diehl Anna Mae, Jung Youngmi
Department of Biological Sciences, College of Natural Science, Pusan National University, Pusandaehak-ro 63 beon-gil, Geumjeong-gu, Pusan, 609-735, Korea.
J Mol Histol. 2014 Feb;45(1):103-12. doi: 10.1007/s10735-013-9532-5. Epub 2013 Aug 15.
Recent studies have reported that NF-κB mediated down-regulation of miRNA-29 and lower expression of miRNA-29 promoted the deposition of collagens in fibrotic liver. Our previous research demonstrated that the increased Hedgehog (Hh) signaling, a key regulator for hepatic fibrogenesis, induced the severe hepatic fibrosis in the livers with impaired NF-κB signaling. These findings led us to investigate the effect of Hh and miRNA-29 on the hepatic fibrosis under dysregulated NF-κB signaling. In this study, we used IKKβ(F/F) and IKKβ-deficient IKKβ(ΔHEP) mouse model with a defective NF-κB signaling pathway, and assessed the expression of the miRNA-29 family (miRNA-29a, miRNA-29b, and miRNA-29c), Hh, and proliferation of MF-HSCs in liver from IKKβ(F/F) mice and IKKβ(ΔHEP) mice both before and after MCDE treatment. The activation of NF-κB was significantly increased in MCDE diet-fed IKKβ(F/F) mice compared to IKKβ(ΔHEP) mice. Expression of miRNA-29 family was greater in MCDE diet-fed IKKβ(ΔHEP) mice than IKKβ(F/F) mice, demonstrating that the impaired NF-κB pathway was unable to suppress the expression of miRNA-29s after injury. However, expression of the Hh signaling pathway was greatly enhanced, and activation of Hh promoted the accumulation of MF-HSCs with impaired NF-κB, eventually increasing fibrogenesis in the damaged liver of IKKβ(ΔHEP) mice. Therefore, these results demonstrated that Hh signaling regulates the proliferation of MF-HSCs irrespective of the action of miRNA-29, eventually contributing hepatic fibrosis, when the NF-κB pathway is disrupted.
近期研究报道，核因子-κB（NF-κB）介导的微小RNA-29（miRNA-29）下调以及miRNA-29的低表达促进了肝纤维化中胶原蛋白的沉积。我们之前的研究表明，肝纤维化的关键调节因子刺猬信号通路（Hh）的激活增加，在NF-κB信号受损的肝脏中诱导了严重的肝纤维化。这些发现促使我们研究在NF-κB信号失调的情况下，Hh和miRNA-29对肝纤维化的影响。在本研究中，我们使用了NF-κB信号通路缺陷的IKKβ（F/F）和IKKβ缺陷的IKKβ（ΔHEP）小鼠模型，并评估了在蛋氨酸胆碱缺乏饮食（MCDE）处理前后，IKKβ（F/F）小鼠和IKKβ（ΔHEP）小鼠肝脏中miRNA-29家族（miRNA-29a、miRNA-29b和miRNA-29c）、Hh的表达以及肌成纤维细胞样肝星状细胞（MF-HSCs）的增殖情况。与IKKβ（ΔHEP）小鼠相比，MCDE饮食喂养的IKKβ（F/F）小鼠中NF-κB的激活显著增加。在MCDE饮食喂养的IKKβ（ΔHEP）小鼠中，miRNA-29家族的表达高于IKKβ（F/F）小鼠，表明受损的NF-κB通路在损伤后无法抑制miRNA-29的表达。然而，Hh信号通路的表达显著增强，Hh的激活促进了NF-κB受损的MF-HSCs的积累，最终增加了IKKβ（ΔHEP）小鼠受损肝脏中的纤维化。因此，这些结果表明，当NF-κB通路被破坏时，Hh信号通路无论miRNA-29的作用如何，均调节MF-HSCs的增殖，最终导致肝纤维化。
