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Autophagy Regulates Bile Acid Metabolism via a NRF2‐FXR Signaling Axis
Author(s) -
Khambu Bilon,
Yan Shengmin,
Huda Nazmul,
Liu Gang,
Hong Honghai,
Chen Xiaoyun,
Yin XiaoMing
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.126.3
Subject(s) - autophagy , atg5 , bile acid , metabolism , liver injury , farnesoid x receptor , downregulation and upregulation , cholestasis , bile salt export pump , intracellular , biology , endocrinology , medicine , microbiology and biotechnology , transporter , biochemistry , transcription factor , nuclear receptor , gene , apoptosis
Autophagy is a vital intracellular degradation and recycling process which is required for hepatic metabolic homeostasis. Deficiency of autophagy in the liver causes severe injury that may be causatively related to disturbed metabolism. However, it is not clear how autophagy mechanistically contributes to hepatic metabolism and whether the disturbed hepatic metabolism could be a contributing factor for hepatic injury. Here we found that hepatic deletion of Atg7 or Atg5 resulted in dysregulated bile acid (BA) metabolism, with a downregulation FXR functionality. Reduced FXR resulted in intrahepatic cholestasis due to reduced expression of Bsep , a key bile acid transporter at the apical surface of hepatocytes. Further studies indicated that an excessively high level of NRF2 could transcriptionally repress the expression of FXR. Pharmacologically or genetic activation of FXR in autophagy‐deficient liver corrected the BA metabolism and hence alleviated the cholestatic liver injury. Thus, excessive activation of Nrf2 mediated FXR repression is responsible for the dysregulation of BA metabolism and hence the cholestatic liver injury. This exciting new finding suggests that autophagy regulates hepatic metabolism beyond nutrients breakdown by controlling the NRF2‐FXR signaling components. Support or Funding Information Department of Pathology and Laboratory Medicine, Indiana University School of Medicine This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .