Biomedical Research Center, Southern Medical University, Guangzhou, China; Medical Research Center of Nanfang Hospital, Southern Medical University, Guangzhou, China; School of Pharmaceutical Science, Southern Medical University, Guangzhou, China.
Biomedical Research Center, Southern Medical University, Guangzhou, China; School of Pharmaceutical Science, Southern Medical University, Guangzhou, China.
Cell Mol Gastroenterol Hepatol. 2022;14(5):1123-1145. doi: 10.1016/j.jcmgh.2022.07.016. Epub 2022 Aug 8.
BACKGROUND & AIMS: Glia maturation factor-β (GMFB) is a bona fide member of the actin depolymerizing factor homology family. Recently, emerging evidence suggested its implication in liver diseases, but data on its role in liver remain limited.
Assessment of GMFB in liver histology, impact on liver regeneration and hepatocyte proliferation, and the underlying molecular pathways were conducted using mouse models with acute liver injury.
GMFB is widely distributed in normal liver. Its expression increases within 24 hours after partial hepatectomy (PHx). Adult Gmfb knockout mice and wild-type littermates are similar in gross appearance, body weight, liver function, and histology. However, compared with wild-type control, Gmfb knockout mice post-PHx develop more serious liver damage and steatosis and have delayed liver regeneration; the dominant change in liver transcriptome at 24 hours after PHx is the significantly suppressed acute inflammation pathways; the top down-regulated gene sets relate to interleukin (IL)6/Janus kinase/signal transducer and activator of transcription 3 (STAT3) signaling. Another mouse model intoxicated with carbon tetrachloride replicated these findings. Furthermore, Gmfb knockout and wild-type groups have the similar numbers of Kupffer cells, but Gmfb knockout Kupffer cells once stimulated produce less IL6, tumor necrosis factor, and IL1β. In hepatocytes treated with IL6, GMFB associates positively with cell proliferation and STAT3/cyclin D1 activation, but without any direct interaction with STAT3. In Gmfb knockout hepatocytes, cytoskeleton-related gene expression was changed significantly, with an abnormal-appearing morphology of actin networks. In hepatocyte modeling, actin-filament turnover, STAT3 activation, and metabolite excretion show a strong reliance on the status of actin-filament organization.
GMFB plays a significant role in liver regeneration by promoting acute inflammatory response in Kupffer cells and by intracellularly coordinating the responsive hepatocyte proliferation.
胶质细胞成熟因子-β（GMFB）是肌动蛋白解聚因子同源家族的一个真正成员。最近，新出现的证据表明其与肝脏疾病有关，但有关其在肝脏中的作用的数据仍然有限。
使用急性肝损伤的小鼠模型评估 GMFB 在肝组织学中的表达、对肝再生和肝细胞增殖的影响，以及潜在的分子途径。
GMFB 在正常肝脏中广泛分布。其表达在部分肝切除（PHx）后 24 小时内增加。成年 Gmfb 敲除小鼠和野生型同窝仔鼠在外观、体重、肝功能和组织学上相似。然而，与野生型对照相比，Gmfb 敲除小鼠在 PHx 后发生更严重的肝损伤和脂肪变性，并且肝再生延迟；PHx 后 24 小时肝转录组的主要变化是明显抑制急性炎症途径；下调基因集与白细胞介素（IL）6/Janus 激酶/信号转导和转录激活因子 3（STAT3）信号有关。另一个用四氯化碳中毒的小鼠模型复制了这些发现。此外，Gmfb 敲除和野生型组的枯否细胞数量相同，但 Gmfb 敲除的枯否细胞一旦受到刺激，产生的 IL6、肿瘤坏死因子和 IL1β 较少。在接受 IL6 处理的肝细胞中，GMFB 与细胞增殖和 STAT3/细胞周期蛋白 D1 激活呈正相关，但与 STAT3 无直接相互作用。在 Gmfb 敲除的肝细胞中，细胞骨架相关基因的表达发生了显著变化，肌动蛋白网络呈现异常形态。在肝细胞建模中，肌动蛋白丝周转、STAT3 激活和代谢产物排泄强烈依赖于肌动蛋白丝组织的状态。
GMFB 通过促进枯否细胞的急性炎症反应和细胞内协调应答性肝细胞增殖，在肝再生中发挥重要作用。
