Hepatic Deletion of X-Box Binding Protein 1 in FXR Null Mice Leads to Enhanced Liver Injury.

Autor:	Liu X; Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. Electronic address: xiaoying-liu@northwestern.edu., Khalafalla M; Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Chung C; Gilead Sciences, Inc, Foster City, CA, USA., Gindin Y; Gilead Sciences, Inc, Foster City, CA, USA., Hubchak S; Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., LeCuyer B; Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Kriegermeier A; Division of Gastroenterology, Department of Pediatrics, Feinberg School of Medicine, Hepatology and Nutrition at Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University, Chicago, IL, USA., Zhang D; Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Qiu W; Department of Surgery & Department of Cancer Biology, Loyola University Chicago, Maywood, IL, USA., Ding X; Department of Pathology, Stritch Medicine school of Loyola University Chicago, Maywood, IL, USA., Fang D; Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA., Green R; Division of Gastroenterology and Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Jazyk:	angličtina
Zdroj:	Journal of lipid research [J Lipid Res] 2022 Nov; Vol. 63 (11), pp. 100289. Date of Electronic Publication: 2022 Sep 24.
DOI:	10.1016/j.jlr.2022.100289
Abstrakt:	FXR regulates bile acid metabolism, and FXR null (Fxr -/- ) mice have elevated bile acid levels and progressive liver injury. The inositol-requiring enzyme 1α/X-box binding protein 1 (XBP1) pathway is a protective unfolded protein response pathway activated in response to endoplasmic reticulum stress. Here, we sought to determine the role of the inositol-requiring enzyme 1α/XBP1 pathway in hepatic bile acid toxicity using the Fxr -/- mouse model. Western blotting and quantitative PCR analysis demonstrated that hepatic XBP1 and other unfolded protein response pathways were activated in 24-week-old Fxr -/- compared with 10-week-old Fxr -/- mice but not in WT mice. To further determine the role of the liver XBP1 activation in older Fxr -/- mice, we generated mice with whole-body FXR and liver-specific XBP1 double KO (DKO, Fxr -/- Xbp1 LKO ) and Fxr -/- Xbp1 fl/fl single KO (SKO) mice and characterized the role of hepatic XBP1 in cholestatic liver injury. Histologic staining demonstrated increased liver injury and fibrosis in DKO compared with SKO mice. RNA sequencing revealed increased gene expression in apoptosis, inflammation, and cell proliferation pathways in DKO mice. The proapoptotic C/EBP-homologous protein pathway and cell cycle marker cyclin D1 were also activated in DKO mice. Furthermore, we found that total hepatic bile acid levels were similar between the two genotypes. At age 60 weeks, all DKO mice and no SKO mice spontaneously developed liver tumors. In conclusion, the hepatic XBP1 pathway is activated in older Fxr -/- mice and has a protective role. The potential interaction between XBP1 and FXR signaling may be important in modulating the hepatocellular cholestatic stress responses. Competing Interests: Conflict of interest C. C. and Y. G. were employees of Gilead Sciences, Inc during the drafting of this article. All other authors declare that they have no conflicts of interest with the contents of this article. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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