■肝细胞核因子4α(HNF4α)是肝分化的主要调节因子。最近的研究也揭示了HNF4α通过负调控促有丝分裂基因的表达在肝细胞增殖中的作用。包括cMyc.这里,我们旨在研究HNF4α-cMyc在肝部分切除术(PHX)后肝再生过程中的相互作用。
■野生型(WT),肝细胞特异性敲除HNF4α(HNF4α-KO),cMyc(cMyc-KO),对HNF4α-cMyc双敲除(DKO)小鼠进行PHX以诱导肝再生。0h时收集血液和肝组织样本,24h,48h,7D,和PHX后的14D用于进一步分析。
■WT,HNF4α-KO,cMyc-KO和DKO小鼠在PHX后14天恢复肝脏重量。cMyc的缺失不影响肝再生,这与WT小鼠相似。WT和cMyc-KO小鼠早在PHX后24小时就开始恢复肝脏重量,在PHX后48小时出现峰值增殖反应。HNF4α-KO和DKO在PHX后第7天显示肝脏重量增加的延迟反应。PHX后DKO小鼠的总体肝细胞增殖反应低于其他基因型。有趣的是,存活的HNF4α-KO和DKO小鼠在PHX后第14天显示HNF4αmRNA和蛋白水平的再表达。这伴随着Krt19和Epcam表达的显着增加,肝祖细胞标志物,在PHX后第14天的DKO小鼠中。
■这些数据表明,在没有HNF4α的情况下,cMyc有助于肝细胞驱动的增殖以补偿丢失的组织质量。此外,在没有HNF4α和cMyc的情况下,发生HPC驱动的增殖以支持肝再生。
UNASSIGNED: Hepatocyte nuclear factor 4 alpha (HNF4α) is the master regulator of hepatic differentiation. Recent studies have also revealed the role of HNF4α in hepatocyte proliferation via negatively regulating the expression of proto-mitogenic genes, including cMyc. Here, we aimed to study the interaction between HNF4α-cMyc during liver regeneration after partial hepatectomy (PHX).
UNASSIGNED: Wild-type (WT), hepatocyte-specific knockout of HNF4α (HNF4α-KO), cMyc (cMyc-KO), and HNF4α-cMyc double knockout (DKO) mice were subjected to PHX to induce liver regeneration. Blood and liver tissue samples were collected at 0h, 24h, 48h, 7D, and 14D after PHX for further analysis.
UNASSIGNED: WT, HNF4α-KO, cMyc-KO and DKO mice regained liver weight by 14 days after PHX. The deletion of cMyc did not affect liver regeneration, which was similar to the WT mice. WT and cMyc-KO mice started regaining liver weight as early as 24 hours after PHX, with a peak proliferation response at 48 hours after PHX. HNF4α- KO and DKO showed a delayed response with liver weight increase by day 7 after PHX. The overall hepatocyte proliferation response by DKO mice following PHX was lower than that of other genotypes. Interestingly, the surviving HNF4α-KO and DKO mice showed re-expression of HNF4α at mRNA and protein levels on day 14 after PHX. This was accompanied by a significant increase in the expression of Krt19 and Epcam, hepatic progenitor cell markers, in the DKO mice on day 14 after PHX.
UNASSIGNED: These data indicate that, in the absence of HNF4α, cMyc contributes to hepatocyte-driven proliferation to compensate for the lost tissue mass. Furthermore, in the absence of both HNF4α and cMyc, HPC-driven proliferation occurs to support liver regeneration.