PDF(Pubmed)
Abstract：
Hereditary tyrosinemia type 1 (HT1) is a genetic disorder of the tyrosine degradation pathway (TIMD) with unmet therapeutic needs. HT1 patients are unable to fully break down the amino acid tyrosine due to a deficient fumarylacetoacetate hydrolase (FAH) enzyme and, therefore, accumulate toxic tyrosine intermediates. If left untreated, they experience hepatic failure with comorbidities involving the renal and neurological system and the development of hepatocellular carcinoma (HCC). Nitisinone (NTBC), a potent inhibitor of the 4-hydroxyphenylpyruvate dioxygenase (HPD) enzyme, rescues HT1 patients from severe illness and death. However, despite its demonstrated benefits, HT1 patients under continuous NTBC therapy are at risk to develop HCC and adverse reactions in the eye, blood and lymphatic system, the mechanism of which is poorly understood. Moreover, NTBC does not restore the enzymatic defects inflicted by the disease nor does it cure HT1. Here, the changes in molecular pathways associated to the development and progression of HT1-driven liver disease that remains uncorrected under NTBC therapy were investigated using whole transcriptome analyses on the livers of Fah- and Hgd-deficient mice under continuous NTBC therapy and after seven days of NTBC therapy discontinuation. Alkaptonuria (AKU) was used as a tyrosine-inherited metabolic disorder reference disease with non-hepatic manifestations. The differentially expressed genes were enriched in toxicological gene classes related to liver disease, liver damage, liver regeneration and liver cancer, in particular HCC. Most importantly, a set of 25 genes related to liver disease and HCC development was identified that was differentially regulated in HT1 vs. AKU mouse livers under NTBC therapy. Some of those were further modulated upon NTBC therapy discontinuation in HT1 but not in AKU livers. Altogether, our data indicate that NTBC therapy does not completely resolves HT1-driven liver disease and supports the sustained risk to develop HCC over time as different HCC markers, including Moxd1, Saa, Mt, Dbp and Cxcl1, were significantly increased under NTBC.
摘要：
1型遗传性酪氨酸血症（HT1）是酪氨酸降解途径（TIMD）的遗传性疾病，具有未满足的治疗需求。HT1患者由于缺乏富马酸乙酰乙酸水解酶（FAH）酶而无法完全分解氨基酸酪氨酸，因此,积累有毒的酪氨酸中间体。如果不及时治疗，他们经历肝功能衰竭，并伴有涉及肾脏和神经系统的合并症以及肝细胞癌（HCC）的发展。Nitisinone(NTBC),4-羟苯基丙酮酸双加氧酶（HPD）酶的有效抑制剂，从严重疾病和死亡中拯救HT1患者。然而,尽管它已经证明了好处，HT1患者在连续NTBC治疗的风险发展肝癌和不良反应的眼睛，血液和淋巴系统，其机制知之甚少。此外，NTBC不能恢复疾病造成的酶缺陷，也不能治愈HT1。这里,在NTBC治疗下和NTBC治疗停止7天后,对Fah和Hgd缺陷小鼠肝脏进行全转录组分析,研究了与HT1驱动的肝脏疾病发生和进展相关的分子通路的变化,这些变化在NTBC治疗下仍未纠正.碱性尿症（AKU）被用作具有非肝表现的酪氨酸遗传性代谢紊乱参考疾病。差异表达的基因富集在与肝脏疾病相关的毒理学基因类别中，肝损伤,肝再生和肝癌，特别是HCC。最重要的是,确定了一组25个与肝病和HCC发展相关的基因，这些基因在HT1与NTBC治疗下的AKU小鼠肝脏。在HT1但在AKU肝脏中不停止NTBC治疗后，其中一些被进一步调节。总之,我们的数据表明，NTBC治疗不能完全解决HT1驱动的肝病，并支持随着时间的推移发展为不同的HCC标志物的持续风险。包括Moxd1Saa,Mt,在NTBC下Dbp和Cxcl1显著增加。
