Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
Cell Mol Gastroenterol Hepatol. 2024;17(3):453-479. doi: 10.1016/j.jcmgh.2023.11.009. Epub 2023 Nov 21.
BACKGROUND & AIMS: HNF4α, a master regulator of liver development and the mature hepatocyte phenotype, is down-regulated in chronic and inflammatory liver disease. We used contemporary transcriptomics and epigenomics to study the cause and effects of this down-regulation and characterized a multicellular etiology.
Progressive changes in the rat carbon tetrachloride model were studied by deep RNA sequencing and genome-wide chromatin immunoprecipitation sequencing analysis of transcription factor (TF) binding and chromatin modification. Studies compared decompensated cirrhosis with liver failure after 26 weeks of treatment with earlier compensated cirrhosis and with additional rat models of chronic fibrosis. Finally, to resolve cell-specific responses and intercellular signaling, we compared transcriptomes of liver, nonparenchymal, and inflammatory cells.
HNF4α was significantly lower in 26-week cirrhosis, part of a general reduction of TFs that regulate metabolism. Nevertheless, increased binding of HNF4α contributed to strong activation of major phenotypic genes, whereas reduced binding to other genes had a moderate phenotypic effect. Decreased Hnf4a expression was the combined effect of STAT3 and nuclear factor kappa B (NFκB) activation, which similarly reduced expression of other metabolic TFs. STAT/NFκB also induced de novo expression of Osmr by hepatocytes to complement induced expression of Osm by nonparenchymal cells.
Liver decompensation by inflammatory STAT3 and NFκB signaling was not a direct consequence of progressive cirrhosis. Despite significant reduction of Hnf4a expression, residual levels of this abundant TF still stimulated strong new gene expression. Reduction of HNF4α was part of a broad hepatocyte transcriptional response to inflammation.
HNF4α 是肝脏发育和成熟肝细胞表型的主要调节因子，在慢性和炎症性肝病中下调。我们使用当代转录组学和表观基因组学来研究这种下调的原因和影响，并对多细胞病因进行了特征描述。
通过深度 RNA 测序和转录因子 (TF) 结合和染色质修饰的全基因组染色质免疫沉淀测序分析，研究了大鼠四氯化碳模型中的渐进性变化。研究比较了失代偿性肝硬化与 26 周治疗后发生肝衰竭的情况，以及与慢性纤维化的其他大鼠模型的情况。最后，为了解决细胞特异性反应和细胞间信号传递问题，我们比较了肝脏、非实质和炎症细胞的转录组。
26 周肝硬化时 HNF4α 显著降低，这是调节代谢的 TF 普遍减少的一部分。然而，HNF4α 的结合增加有助于主要表型基因的强烈激活，而对其他基因的结合减少则具有中等表型效应。Hnf4a 表达的降低是 STAT3 和核因子 kappa B (NFκB) 激活的共同作用，这同样降低了其他代谢 TF 的表达。STAT/NFκB 还诱导肝细胞中新的 Osmr 表达，以补充非实质细胞诱导的 Osm 表达。
炎症性 STAT3 和 NFκB 信号导致的肝失代偿不是进行性肝硬化的直接后果。尽管 Hnf4a 表达显著降低，但这种丰富 TF 的残留水平仍能刺激强烈的新基因表达。HNF4α 的减少是肝细胞对炎症的广泛转录反应的一部分。
