Serum transferrin as a biomarker of hepatocyte nuclear factor 4 alpha activity and hepatocyte function in liver diseases.
Serum transferrin as a biomarker of hepatocyte nuclear factor 4 alpha activity and hepatocyte function in liver diseases.
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DOI：
10.1186/s12916-021-01917-6
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发表时间：
2021-02-17
期刊：
影响因子：
9.3
通讯作者：
Strnad P
中科院分区：
文献类型：
--
作者：
Guldiken N;Argemi J;Gurbuz B;Atkinson SR;Oliverius M;Fila P;Hamesch K;Bruns T;Cabezas J;Lozano JJ;Mann J;Cao S;Mathurin P;Shah VH;Trautwein C;Thursz MR;Bataller R;Strnad P
血清转铁蛋白水平是肝衰竭患者死亡率的独立预测因子。肝细胞核因子 4 α (HNF4α) 是肝细胞功能的主要调节因子。本研究的目的是探讨血清转铁蛋白是否反映HNF4α活性。通过转录组学/甲基组学分析以及染色质免疫沉淀与 DNA 测序结合评估调节酒精性肝炎 (AH) 中转铁蛋白表达的因素。这些发现在原代肝细胞中得到了证实。还研究了 40 名患有多种病因的晚期肝病患者的血清和肝脏样本。在晚期肝病患者中，血清转铁蛋白水平与肝脏转铁蛋白表达相关（r = 0.51，p = 0.01）。免疫组织化学和生化测试证实，肝硬化患者的 HNF4α 和转铁蛋白水平降低。在 AH 中，肝脏转录组中的肝基因-基因相关性分析显示，转铁蛋白相关转录组中 HNF4α 特征富集，而转化生长因子 β 1 (TGFβ1)、肿瘤坏死因子 α (TNFα)、白细胞介素 1 β (IL-1β) 和白细胞介素 6 (IL-6) 与转铁蛋白特征呈负相关。 AH 患者中转铁蛋白启动子的一个关键调控区域高度甲基化。在原代肝细胞中，用 TGFβ1 或 HNF4α 抑制剂 BI6015 治疗可抑制转铁蛋白的产生，而暴露于 TNFα、IL-1β 和 IL-6 则没有效果。在晚期肝病中也观察到肝脏 HNF4A 和转铁蛋白 mRNA 水平之间的相关性。血清转铁蛋白水平构成预后和机制生物标志物。因此，它们可以作为肝脏 HNF4α 信号传导受损和肝衰竭的替代品。在线版本包含可在 10.1186/s12916-021-01917-6 获取的补充材料。
Serum transferrin levels represent an independent predictor of mortality in patients with liver failure. Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of hepatocyte functions. The aim of this study was to explore whether serum transferrin reflects HNF4α activity. Factors regulating transferrin expression in alcoholic hepatitis (AH) were assessed via transcriptomic/methylomic analysis as well as chromatin immunoprecipitation coupled to DNA sequencing. The findings were corroborated in primary hepatocytes. Serum and liver samples from 40 patients with advanced liver disease of multiple etiologies were also studied. In patients with advanced liver disease, serum transferrin levels correlated with hepatic transferrin expression (r = 0.51, p = 0.01). Immunohistochemical and biochemical tests confirmed reduced HNF4α and transferrin protein levels in individuals with cirrhosis. In AH, hepatic gene-gene correlation analysis in liver transcriptome revealed an enrichment of HNF4α signature in transferrin-correlated transcriptome while transforming growth factor beta 1 (TGFβ1), tumor necrosis factor α (TNFα), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6) negatively associated with transferrin signature. A key regulatory region in transferrin promoter was hypermethylated in patients with AH. In primary hepatocytes, treatment with TGFβ1 or the HNF4α inhibitor BI6015 suppressed transferrin production, while exposure to TNFα, IL-1β, and IL-6 had no effect. The correlation between hepatic HNF4A and transferrin mRNA levels was also seen in advanced liver disease. Serum transferrin levels constitute a prognostic and mechanistic biomarker. Consequently, they may serve as a surrogate of impaired hepatic HNF4α signaling and liver failure. The online version contains supplementary material available at 10.1186/s12916-021-01917-6.
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影响因子：
3.9
作者：
Peters TJ;Buckley MJ;Statham AL;Pidsley R;Samaras K;V Lord R;Clark SJ;Molloy PL
通讯作者：
Molloy PL
影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
Matei, Daniela
DOI：
10.14309/ajg.0000000000000492
发表时间：
2020-03
期刊：
The American journal of gastroenterology
影响因子：
--
作者：
通讯作者：
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影响因子：
82.9
作者：
Li, Huihui;Rybicki, Anne C.;Ginzburg, Yelena Z.
通讯作者：
Ginzburg, Yelena Z.