Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.
Hepatology. 2023 Oct 1;78(4):1106-1117. doi: 10.1097/HEP.0000000000000367. Epub 2023 Apr 7.
Overdose of acetaminophen (APAP) is the major cause of acute liver failure in the western world. We report a novel signaling interaction between hepatocyte nuclear factor 4 alpha (HNF4α) cMyc and nuclear factor erythroid 2-related factor 2 (Nrf2) during liver injury and regeneration after APAP overdose.
APAP-induced liver injury and regeneration were studied in male C57BL/6J (WT) mice, hepatocyte-specific HNF4α knockout mice (HNF4α-KO), and HNF4α-cMyc double knockout mice (DKO). C57BL/6J mice treated with 300 mg/kg maintained nuclear HNF4α expression and exhibited liver regeneration, resulting in recovery. However, treatment with 600-mg/kg APAP, where liver regeneration was inhibited and recovery was delayed, showed a rapid decline in HNF4α expression. HNF4α-KO mice developed significantly higher liver injury due to delayed glutathione recovery after APAP overdose. HNF4α-KO mice also exhibited significant induction of cMyc, and the deletion of cMyc in HNF4α-KO mice (DKO mice) reduced the APAP-induced liver injury. The DKO mice had significantly faster glutathione replenishment due to rapid induction in Gclc and Gclm genes. Coimmunoprecipitation and ChIP analyses revealed that HNF4α interacts with Nrf2 and affects its DNA binding. Furthermore, DKO mice showed significantly faster initiation of cell proliferation resulting in rapid liver regeneration and recovery.
These data show that HNF4α interacts with Nrf2 and promotes glutathione replenishment aiding in recovery from APAP-induced liver injury, a process inhibited by cMyc. These studies indicate that maintaining the HNF4α function is critical for regeneration and recovery after APAP overdose.
在西方世界，对乙酰氨基酚（APAP）的过量使用是导致急性肝衰竭的主要原因。我们报道了一种新的信号转导相互作用，即肝细胞核因子 4α（HNF4α）cMyc 和核因子红细胞 2 相关因子 2（Nrf2）在 APAP 过量使用后肝损伤和再生期间。
在雄性 C57BL/6J（WT）小鼠、肝细胞特异性 HNF4α 敲除小鼠（HNF4α-KO）和 HNF4α-cMyc 双敲除小鼠（DKO）中研究了 APAP 诱导的肝损伤和再生。用 300mg/kg 的 C57BL/6J 小鼠处理后维持核 HNF4α 的表达，并表现出肝再生，从而恢复。然而，用 600mg/kg 的 APAP 处理，其中肝再生被抑制且恢复被延迟，表现出 HNF4α 表达的快速下降。由于 APAP 过量后谷胱甘肽的恢复延迟，HNF4α-KO 小鼠发生了明显更高的肝损伤。HNF4α-KO 小鼠也表现出 cMyc 的显著诱导，并且在 HNF4α-KO 小鼠（DKO 小鼠）中删除 cMyc 减少了 APAP 诱导的肝损伤。由于 Gclc 和 Gclm 基因的快速诱导，DKO 小鼠的谷胱甘肽补充更快。共免疫沉淀和 ChIP 分析显示 HNF4α 与 Nrf2 相互作用并影响其 DNA 结合。此外，DKO 小鼠显示出更快的细胞增殖启动，导致更快的肝再生和恢复。
这些数据表明 HNF4α 与 Nrf2 相互作用并促进谷胱甘肽的补充，有助于从 APAP 诱导的肝损伤中恢复，该过程受 cMyc 抑制。这些研究表明，维持 HNF4α 的功能对于 APAP 过量后再生和恢复至关重要。
