小柯机器人

美国诺华生物医学研究所Jan S. Tchorz、Tianliang Sun等研究人员合作发现，ZNRF3和RNF43合作保护代谢性肝分区和肝细胞增殖。该研究于2021年6月14日在线发表于国际一流学术期刊《细胞—干细胞》。

研究人员表示，AXIN2和LGR5标记肠道干细胞（ISC），它们需要WNT/β-Catenin信号来实现持续的稳态增殖。相比之下，尽管代谢性肝分区需要WNT/β-Catenin活性梯度，但AXIN2/LGR5+周围肝细胞显示出低增殖率。限制 AXIN2+肝细胞增殖和AXIN2+ ISC代谢基因表达的机制仍不清楚。

研究人员表明，ISC中染色质可及性的限制阻止了β-Catenin调节的代谢酶的表达，而ZNRF3和RNF43对WNT/β-Catenin活性的微调限制了AXIN2+肝细胞的增殖，同时保留了代谢功能。ZNRF3缺失促进肝细胞增殖，这反过来又受到RNF43上调的限制。ZNRF3突变小鼠中RNF43的伴随缺失导致门静脉周围肝细胞的代谢重编程并诱导肝细胞亚群的克隆扩增，最终促进肝脏肿瘤。ZNRF3和RNF43通过在空间和时间上限制WNT/β-Catenin活性、平衡代谢功能和肝细胞增殖来共同保护肝脏稳态。

附：英文原文

Title: ZNRF3 and RNF43 cooperate to safeguard metabolic liver zonation and hepatocyte proliferation

Author: Tianliang Sun, Stefano Annunziato, Sebastian Bergling, Caibin Sheng, Vanessa Orsini, Pascal Forcella, Monika Pikiolek, Venkatesh Kancherla, Sjoerd Holwerda, Dilek Imanci, Fabian Wu, Ludivine Challet Meylan, Lea F. Puehringer, Annick Waldt, Mevion Oertli, Sven Schuierer, Luigi M. Terracciano, Stefan Reinker, Heinz Ruffner, Tewis Bouwmeester, Andreas W. Sailer, Elizabeth George, Guglielmo Roma, Antoine de Weck, Salvatore Piscuoglio, Felix Lohmann, Ulrike Naumann, Prisca Liberali, Feng Cong, Jan S. Tchorz

Issue&Volume: 2021-06-14

Abstract: AXIN2 and LGR5 mark intestinal stem cells (ISCs) that require WNT/β-Catenin signalingfor constant homeostatic proliferation. In contrast, AXIN2/LGR5+ pericentral hepatocytesshow low proliferation rates despite a WNT/β-Catenin activity gradient required formetabolic liver zonation. The mechanisms restricting proliferation in AXIN2+ hepatocytesand metabolic gene expression in AXIN2+ ISCs remained elusive. We now show that restrictedchromatin accessibility in ISCs prevents the expression of β-Catenin-regulated metabolicenzymes, whereas fine-tuning of WNT/β-Catenin activity by ZNRF3 and RNF43 restrictsproliferation in chromatin-permissive AXIN2+ hepatocytes, while preserving metabolicfunction. ZNRF3 deletion promotes hepatocyte proliferation, which in turn becomeslimited by RNF43 upregulation. Concomitant deletion of RNF43 in ZNRF3 mutant miceresults in metabolic reprogramming of periportal hepatocytes and induces clonal expansionin a subset of hepatocytes, ultimately promoting liver tumors. Together, ZNRF3 andRNF43 cooperate to safeguard liver homeostasis by spatially and temporally restrictingWNT/β-Catenin activity, balancing metabolic function and hepatocyte proliferation.

DOI: 10.1016/j.stem.2021.05.013

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00250-2

Cell Stem Cell：《细胞—干细胞》，创刊于2007年。隶属于细胞出版社，最新IF：25.269
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