Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Beijing Institute of Hepatology, Beijing You'an Hospital, Capital Medical University, Beijing, China.
Gut. 2023 Mar;72(3):549-559. doi: 10.1136/gutjnl-2022-326987. Epub 2022 Apr 20.
Multidrug resistance protein 2 (MRP2) is a bottleneck in bilirubin excretion. Its loss is sufficient to induce hyperbilirubinaemia, a prevailing characteristic of acute liver failure (ALF) that is closely associated with clinical outcome. This study scrutinises the transcriptional regulation of MRP2 under different pathophysiological conditions.
Hepatic MRP2, farnesoid X receptor (FXR) and Forkhead box A2 (FOXA2) expression and clinicopathologic associations were examined by immunohistochemistry in 14 patients with cirrhosis and 22 patients with ALF. MRP2 regulatory mechanisms were investigated in primary hepatocytes, mice and lipopolysaccharide (LPS)-treated mice.
Physiologically, homeostatic MRP2 transcription is mediated by the nuclear receptor FXR/retinoid X receptor complex. mice lack apical MRP2 expression and rapidly progress into hyperbilirubinaemia. In patients with ALF, hepatic FXR expression is undetectable, however, patients without infection maintain apical MRP2 expression and do not suffer from hyperbilirubinaemia. These patients express FOXA2 in hepatocytes. FOXA2 upregulates MRP2 transcription through binding to its promoter. Physiologically, nuclear FOXA2 translocation is inhibited by insulin. In ALF, high levels of glucagon and tumour necrosis factor α induce FOXA2 expression and nuclear translocation in hepatocytes. Impressively, ALF patients with sepsis express low levels of FOXA2, lose MRP2 expression and develop severe hyperbilirubinaemia. In this case, LPS inhibits FXR expression, induces FOXA2 nuclear exclusion and thus abrogates the compensatory MRP2 upregulation. In both and LPS-treated mice, ectopic FOXA2 expression restored apical MRP2 expression and normalised serum bilirubin levels.
FOXA2 replaces FXR to maintain MRP2 expression in ALF without sepsis. Ectopic FOXA2 expression to maintain MRP2 represents a potential strategy to prevent hyperbilirubinaemia in septic ALF.
多药耐药相关蛋白 2（MRP2）是胆红素排泄的一个瓶颈。其缺失足以导致高胆红素血症，这是急性肝衰竭（ALF）的一个主要特征，与临床预后密切相关。本研究探讨了不同病理生理条件下 MRP2 的转录调控。
采用免疫组织化学法检测 14 例肝硬化和 22 例 ALF 患者肝组织 MRP2、法尼醇 X 受体（FXR）和叉头框蛋白 A2（FOXA2）的表达及其与临床病理的关系。在原代肝细胞、小鼠和脂多糖（LPS）处理的小鼠中研究了 MRP2 的调控机制。
在生理状态下，稳态 MRP2 转录由核受体 FXR/视黄醇 X 受体复合物介导。Foxa2 基因敲除小鼠缺乏顶膜 MRP2 表达，迅速发展为高胆红素血症。在 ALF 患者中，肝 FXR 表达检测不到，但无感染的患者仍保持顶膜 MRP2 表达，不发生高胆红素血症。这些患者的肝细胞中表达 FOXA2。FOXA2 通过与启动子结合而上调 MRP2 转录。在生理状态下，FOXA2 的核转位受胰岛素抑制。在 ALF 中，高浓度的胰高血糖素和肿瘤坏死因子-α诱导肝细胞中 FOXA2 的表达和核转位。令人印象深刻的是，伴有脓毒症的 ALF 患者表达低水平的 FOXA2，失去 MRP2 表达并发生严重高胆红素血症。在这种情况下，LPS 抑制 FXR 表达，诱导 FOXA2 核输出，从而取消了代偿性 MRP2 上调。在 Foxa2 基因敲除小鼠和 LPS 处理的小鼠中，异位 FOXA2 表达恢复了顶膜 MRP2 表达并使血清胆红素水平正常化。
在无脓毒症的 ALF 中，FOXA2 替代 FXR 维持 MRP2 表达。异位 FOXA2 表达以维持 MRP2 代表了预防脓毒症性 ALF 高胆红素血症的一种潜在策略。
