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Original research
FOXA2 prevents hyperbilirubinaemia in acute liver failure by maintaining apical MRP2 expression
  1. Sai Wang1,
  2. Rilu Feng1,
  3. Shan Shan Wang1,2,
  4. Hui Liu3,
  5. Chen Shao3,
  6. Yujia Li1,
  7. Frederik Link1,
  8. Stefan Munker4,5,
  9. Roman Liebe6,7,
  10. Christoph Meyer1,
  11. Elke Burgermeister1,
  12. Matthias Ebert1,8,9,
  13. Steven Dooley1,
  14. Huiguo Ding10,
  15. Honglei Weng1
  1. 1Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
  2. 2Beijing Institute of Hepatology, Beijing You'an Hospital, Capital Medical University, Beijing, China
  3. 3Department of Pathology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China
  4. 4Department of Medicine II, University Hospital, LMU, Munich, Germany
  5. 5Liver Center Munich, University Hospital, LMU, Munich, Germany
  6. 6Clinic of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University, Düsseldorf, Germany
  7. 7Department of Medicine II, Saarland University Medical Centre, Saarland University, Homburg, Germany
  8. 8Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
  9. 9Clinical Cooperation Unit Healthy Metabolism, Center of Preventive Medicine and Digital Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
  10. 10Department of Gastroenterology and Hepatology, Beijing You’an Hospital, Affiliated with Capital Medical University, Beijing, China
  1. Correspondence to Dr Honglei Weng, Department of Medicine II, Section Molecular Hepatology, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; honglei.weng{at}medma.uni-heidelberg.de

Abstract

Objective 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.

Design 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, Fxr−/− mice and lipopolysaccharide (LPS)-treated mice.

Results Physiologically, homeostatic MRP2 transcription is mediated by the nuclear receptor FXR/retinoid X receptor complex. Fxr−/− 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 Fxr−/− and LPS-treated mice, ectopic FOXA2 expression restored apical MRP2 expression and normalised serum bilirubin levels.

Conclusion 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.

  • ACUTE LIVER FAILURE
  • SEPSIS
  • CHOLESTASIS

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

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Footnotes

  • Contributors HW contributed to conception, design and hypothesis; SW, RF, SSW, YL, FL, SM, CM and EB contributed to in vitro and animal experiments; HL, CS, HD and HW to patients sampling and pathological experiments; SW and HW to drafting the article; SW, RM, CM, EB, ME, SD and HW to data discussion, reviewing and editing the article critically.

  • Funding The study was supported by the Chinese-German Cooperation Group projects GZ 1517 (HW and HD), GZ1263 (SD), M-0099 (SD) and M-0200 (SSW and CM); Deutsche Forschungsgemeinschaft WE 5009/9-1 (HW), Chinese Nature Science Foundation 81970525 (HD) and 81870424 (SSW); and LiSyM Grant PTJ-FKZ: 031L0043 (SD). RL received funding from BMBF through HiChol (01GM1904A). SW and RF are supported by the Chinese Scholarship Council (201708080021 and 201706230256).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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