The role of the HNF4alpha transcription network in the maintenance of key hepatocyte functions during acute liver failure

HNF4α转录网络在急性肝衰竭期间维持关键肝细胞功能中的作用

• 批准号: 515099327
• 负责人: Dr. Honglei Weng, Ph.D.
• 金额: --
• 依托单位: II. Medizinische Klinik: Gastroenterologie, Hepatologie, Infektiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/515099327?language=en
• 关键词: role; HNF4alpha; transcription; network; maintenance

Massive hepatocyte loss results in acute liver failure (ALF), a medical emergency with high mortality worldwide. In such a detrimental condition, performance of essential liver functions by the remaining hepatocytes and activated liver progenitor cells (LPC) is crucial for the survival of patients. As a master hepatic transcription factor, HNF4alpha expression in the remaining hepatocytes and LPC is essential to maintain key liver functions in ALF. To date, the detailed mechanism regulating HNF4alpha under severe disease conditions, such as massive hepatocyte loss and severe inflammation, remains largely unknown. Our recent studies showed that activin induces coagulation factor expression by upregulating HNF4alpha expression in LPC, and thus determines the clinical outcome of ALF. In addition, the binding of HNF4alpha to target genes’ enhancers requires pioneer factor FOXA2 to keep chromatin accessible in both hepatocytes and LPC. Based on these new insights, we propose to investigate the following hypotheses: (1) Supported by pioneer factor FOXA2, HNF4 synergizes with additional transcription factors such as C/EBPalpha to form a transcriptional network in hepatocytes that regulates key functional genes for physiological demand. (2) When severe inflammation inhibits HNF4alpha expression in hepatocytes, FOXA2 coordinates with transcription factors such as RAR to regulate key functional genes. (3) In ALF with MHN, supported by FOXA2 activated LPC initiate an HNF4-dominated transcriptional network to take over key hepatocyte functions in areas in the absence of hepatocytes. To confirm these hypotheses, primary hepatocytes and LPC as well as cell lines will be used for molecular biological investigation in vitro. The role and potential mechanisms of transcription factors in ALF will be examined in vivo in ALF patients, acetaminophen- and LPS combined with D-galactosamine-treated mice and metronidazole-treated zebrafish. Clarification of the exact molecular mechanisms maintaining essential liver functions following massive hepatocyte loss will enhance our understanding of ALF and provide novel targets for therapeutic intervention.

大量肝细胞丢失导致急性肝功能衰竭(ALF)，这是一种全球范围内死亡率很高的紧急医疗事件。在这种有害的条件下，剩余的肝细胞和激活的肝祖细胞(LPC)发挥基本的肝功能对患者的生存至关重要。作为一种主要的肝脏转录因子，HNF4α在剩余的肝细胞和LPC中的表达对于维持ALF中的关键肝功能是必不可少的。到目前为止，在严重疾病条件下调节HNF4α的详细机制仍不清楚，如大量肝细胞丢失和严重炎症。我们最近的研究表明，激活素通过上调LPC中HNF4α的表达来诱导凝血因子的表达，从而决定ALF的临床转归。此外，HNF4pha与靶基因增强子的结合需要先锋因子FOXA2来保持染色质在肝细胞和LPC中的可获得性。基于这些新的见解，我们建议研究以下假设：(1)在先锋因子FOXA2的支持下，HNF4与额外的转录因子如C/EBPalpha协同作用，在肝细胞中形成一个转录网络，调节生理需求的关键功能基因。(2)当严重炎症抑制HNF4α在肝细胞中的表达时，FOXA2与RAR等转录因子协同调节关键功能基因。(3)在伴有MHN的ALF中，在FOXA2激活的LPC的支持下，LPC启动HNF4主导的转录网络，在缺乏肝细胞的区域接管关键的肝细胞功能。为了证实这些假说，我们将使用原代肝细胞和LPC以及细胞系进行体外分子生物学研究。在ALF患者、醋氨酚和脂多糖联合D-氨基半乳糖治疗的小鼠和甲硝唑治疗的斑马鱼中，将在体内研究ALF中转录因子的作用和潜在机制。阐明大量肝细胞丢失后维持基本肝功能的确切分子机制将加深我们对ALF的了解，并为治疗干预提供新的靶点。