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Effects of FXR Deficiency in Acute Phase Response After Bacterial Infection
Author(s) -
Chung Sammi,
Armstrong Laura,
Kong Bo,
Guo Grace L.
Publication year - 2018
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.2018.32.1_supplement.832.4
Subject(s) - farnesoid x receptor , spleen , inflammation , medicine , acute phase protein , nuclear receptor , nonalcoholic fatty liver disease , endocrinology , biology , immunology , transcription factor , fatty liver , gene , biochemistry , disease
Farnesoid X receptor (FXR) is a ligand‐activated nuclear receptor and a transcription factor, regulating bile acid synthesis and transport. FXR is highly expressed in the liver, and more recently FXR has been shown to play a key role in modulating inflammation. Studies have shown that FXR, when activated, acts as a protective agent against liver inflammation and potentially liver diseases such as nonalcoholic steatohepatitis, a part of fatty liver disease. Furthermore, FXR may regulate acute phase proteins, which are secreted as a result of acute phase response (APR)—a systemic reaction that is important for innate immunity and is caused by infection, trauma, or tissue injury. However, the exact mechanism is not well‐established. Thus, the purpose of this study was to investigate the role of FXR in the regulation of the hepatic APR using a bacterial infection model. To understand the mechanism and the effects, hepatocyte‐specific FXR knockout mice (FXR hep −/− ) and wild‐type control mice (WT) were injected with Escherichia coli ( E. coli ) intraperitoneally. Serum, liver, and spleen were isolated 24 hrs following bacterial exposure, and in vivo bacterial counts were determined in whole blood, liver, and spleen. Gene expression of inflammatory cytokines (Tnfα, Il‐1β, Il‐6,) and acute phase proteins (LCN2, Mcp‐1, and Saa3) were measured using quantitative PCR (qPCR) in both liver and spleen. Compared to WT mice, FXR hep −/− mice had significantly increased bacterial load in the liver and spleen following the E.coli treatment, suggesting that they were more susceptible to bacterial infection; however, there was no significant increase in bacterial load in the blood. Serum activities of ALT and AST in FXR hep −/− mice were also elevated, indicating increased liver damage after E.coli treatment. In addition, following the E.coli treatment, gene expression showed a diminished induction of acute phase proteins, Mcp‐1 and Saa3, along with cytokines IL‐1β, IL‐6, and Tnfα in FXR hep −/− mice compared to WT mice. Furthermore, this infection resulted in high levels of LCN2 induction for both the WT and FXR hep −/− mice. In conclusion, the study demonstrates that FXR might be a putative regulator of hepatic acute phase proteins. Support or Funding Information R25ES020721, R01GM104037 and ASPET SURF Intern Program This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .