Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, Kansas, USA.
Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA.
Hepatology. 2022 Aug;76(2):372-386. doi: 10.1002/hep.32326. Epub 2022 Mar 4.
Hepatocyte nuclear factor 4 alpha (HNF4α) is indispensable for hepatocyte differentiation and critical for maintaining liver health. Here, we demonstrate that loss of HNF4α activity is a crucial step in the pathogenesis of chronic liver diseases (CLDs) that lead to development of HCC.
We developed an HNF4α target gene signature, which can accurately determine HNF4α activity, and performed an exhaustive in silico analysis using hierarchical and K-means clustering, survival, and rank-order analysis of 30 independent data sets containing over 3500 individual samples. The association of changes in HNF4α activity to CLD progression of various etiologies, including HCV- and HBV-induced liver cirrhosis (LC), NAFLD/NASH, and HCC, was determined. Results revealed a step-wise reduction in HNF4α activity with each progressive stage of pathogenesis. Cluster analysis of LC gene expression data sets using the HNF4α signature showed that loss of HNF4α activity was associated with progression of Child-Pugh class, faster decompensation, incidence of HCC, and lower survival with and without HCC. A moderate decrease in HNF4α activity was observed in NAFLD from normal liver, but a further significant decline was observed in patients from NAFLD to NASH. In HCC, loss of HNF4α activity was associated with advanced disease, increased inflammatory changes, portal vein thrombosis, and substantially lower survival.
In conclusion, these data indicate that loss of HNF4α function is a common event in the pathogenesis of CLDs leading to HCC and is important from both diagnostic and therapeutic standpoints.
肝细胞核因子 4α（HNF4α）对于肝细胞分化是不可或缺的，对于维持肝脏健康也是至关重要的。在这里，我们证明 HNF4α 活性的丧失是导致 HCC 发生的慢性肝病（CLD）发病机制中的关键步骤。
我们开发了一个 HNF4α 靶基因特征，可以准确地确定 HNF4α 的活性，并使用分层和 K 均值聚类、生存和秩次分析对 30 个独立数据集（包含超过 3500 个个体样本）进行了详尽的计算分析。确定了 HNF4α 活性变化与各种病因引起的 CLD 进展之间的关联，包括 HCV 和 HBV 引起的肝硬化（LC）、NAFLD/NASH 和 HCC。结果显示，随着发病机制的每一个进展阶段，HNF4α 活性逐渐降低。使用 HNF4α 特征对 LC 基因表达数据集进行聚类分析表明，HNF4α 活性的丧失与 Child-Pugh 分级的进展、更快的代偿失调、HCC 的发生以及有无 HCC 的生存率降低有关。在从正常肝脏到 NASH 的 NAFLD 中观察到 HNF4α 活性的适度降低，但在从 NAFLD 到 NASH 的患者中观察到进一步显著降低。在 HCC 中，HNF4α 活性的丧失与晚期疾病、炎症变化增加、门静脉血栓形成以及生存率显著降低有关。
总之，这些数据表明，HNF4α 功能的丧失是导致 HCC 的 CLD 发病机制中的常见事件，从诊断和治疗的角度来看都是重要的。
