Z Gastroenterol 2020; 58(01): e23-e24
DOI: 10.1055/s-0039-3402162
Poster Visit Session III Metabolism (incl. NAFLD): Friday, February 14, 2020, 4:40 pm – 5:25 pm, Lecture Hall P1
Georg Thieme Verlag KG Stuttgart · New York

FOXA2 replaces FXR to maintain BSEP expression on bile canaliculi in acute-on-chronic liver failure

S Wang
1   Mannheim Medical Faculty, Heidelberg University, Mannheim, Germany
,
R Feng
1   Mannheim Medical Faculty, Heidelberg University, Mannheim, Germany
,
S Wang
1   Mannheim Medical Faculty, Heidelberg University, Mannheim, Germany
2   Beijing You'an Hospital, Department of Hepatology, Beijing, China
,
H Liu
2   Beijing You'an Hospital, Department of Hepatology, Beijing, China
,
C Shao
2   Beijing You'an Hospital, Department of Hepatology, Beijing, China
,
MPA Ebert
1   Mannheim Medical Faculty, Heidelberg University, Mannheim, Germany
,
H Ding
2   Beijing You'an Hospital, Department of Hepatology, Beijing, China
,
S Dooley
1   Mannheim Medical Faculty, Heidelberg University, Mannheim, Germany
,
H Weng
1   Mannheim Medical Faculty, Heidelberg University, Mannheim, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2020 (online)

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Background & Aims:

The apical molecule BSEP is a key transporter in charge of bile acid delivery. In physiological conditions, nuclear receptor FXR controls BSEP expression by binding to its promoter. In acute-on-chronic liver failure (ACLF), systemic inflammatory response (SIRS) inhibits FXR expression or leads to loss of FXR nuclear translocation. Interestingly, most hepatocytes of ACLF patients maintain BSEP expression on bile canaliculi. The current study is investigating the regulatory mechanisms underlying BSEP expression in ACLF.

Methods:

We collected liver tissue from 15 ACLF patients. Among them, 10 received liver transplantation and 5 recovered spontaneously. BSEP and transcription factors FXR and FOXA2 were examined by immunohistochemistry. Hepatocellular polarity and BSEP expression regulation were investigated in mouse primary hepatocytes and AML12 cells.

Results:

In the examined ACLF patients regardless of clinical outcome, most hepatocytes maintained BSEP expression on bile canaliculi, although their nuclei do not stain positive for FXR. Instead, BSEP positive hepatocytes robustly express FOXA2 that as well owns binding sites at BSEP promoter. In cultured hepatocytes, ectopic FOXA2 erexpression increases while FOXA2 knockdown reduces BSEP expression. ChIP analysis confirm direct FOXA2 binding to the BSEP promoter. Further, reduced BSEP expression from FXR depleted hepatocytes is completely restored by forced expression of FOXA2. FOXA2 expression and its subcellular localization is regulated by glucagon and insulin. Administration of glucagon to mouse hepatocytes induces FOXA2 expression, therewith maintaining BSEP on the bile canaliculi. On the other hand, insulin treatment remarkably inhibits nuclear translocation of FOXA2 in hepatocytes. These in vitro findings are consistent with clinical observations: (1) The enrolled ACLF patients who express FOXA2 present with high glucagon levels due to SIRS associated high blood glucose. (2) SIRS-induced insulin resistance in liver facilitates FOXA2 nuclear translocation.

Conclusions:

Human body owns two different regulatory systems to respond to physiological or pathological circumstances for maintenance of BSEP on bile canaliculi. FXR controls BSEP expression in physiological conditions. In ACLF with depleted FXR function, FOXA2 maintains BSEP expression and canalicular localization in hepatocytes. FOXA2 expression and subcellular localization are controlled by glucagon and insulin, respectively.