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Farnesoid X receptor signaling activates the hepatic X‐box binding protein 1 pathway in vitro and in mice
Author(s) -
Liu Xiaoying,
Guo Grace L.,
Kong Bo,
Hilburn David B.,
Hubchak Susan C.,
Park Seong,
LeCuyer Brian,
Hsieh Antony,
Wang Li,
Fang Deyu,
Green Richard M.
Publication year - 2018
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.29815
Subject(s) - farnesoid x receptor , in vitro , microbiology and biotechnology , chemistry , nuclear receptor , biology , biochemistry , transcription factor , gene
Bile acids are endogenous ligands of the nuclear receptor, farnesoid X receptor (FXR), and pharmacological FXR modulators are under development for the treatment of several liver disorders. The inositol‐requiring enzyme 1α/X‐box binding protein 1 (IRE1α/XBP1) pathway of the unfolded protein response (UPR) is a protective cellular signaling pathway activated in response to endoplasmic reticulum (ER) stress. We investigated the role of FXR signaling in activation of the hepatic XBP1 pathway. Mice were treated with deoxycholic acid (DCA), cholestyramine, GW4064, or underwent bile duct ligation (BDL), and hepatic UPR activation was measured. Huh7‐Ntcp and HepG2 cells were treated with FXR agonists, inhibitor, small interfering RNA (siRNA), or small heterodimer partner (SHP) siRNA to determine the mechanisms of IRE1α/XBP1 pathway activation. DCA feeding and BDL increased and cholestyramine decreased expression of hepatic XBP1 spliced (XBP1s). XBP1 pathway activation increased in Huh7‐Ntcp and HepG2 cells treated with bile acids, 6α‐ethyl‐chenodeoxycholic acid (6‐ECDCA) or GW4064. This effect decreased with FXR knockdown and treatment with the FXR inhibitor guggulsterone. FXR agonists increased XBP1 splicing and phosphorylated IRE1α ( p ‐IRE1α) expression. Overexpression of SHP similarly increased XBP1 splicing, XBP1s, and p‐IRE1α protein expression. SHP knockdown attenuated FXR agonist‐induced XBP1s and p‐IRE1α protein expression. Co‐immunoprecipitation (Co‐IP) assays demonstrate a physical interaction between overexpressed green fluorescent protein (GFP)‐SHP and FLAG‐IRE1α in HEK293T cells. Mice treated with GW4064 had increased, and FXR and SHP null mice had decreased, basal Xbp1s gene expression. Conclusion : FXR signaling activates the IRE1α/XBP1 pathway in vivo and in vitro . FXR pathway activation increases XBP1 splicing and enhances p‐IRE1α expression. These effects are mediated, at least in part, by SHP. IRE1α/XBP1 pathway activation by bile acids and pharmacological FXR agonists may be protective during liver injury and may have therapeutic implications for liver diseases. (H epatology 2018;68:304‐316).