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Activated farnesoid X receptor attenuates apoptosis and liver injury in autoimmune hepatitis.

Lian F, Wang Y, Xiao Y, Wu X, Xu H, Liang L, Yang X - Mol Med Rep (2015)

Bottom Line: The expression levels of apoptosis‑associated genes and proteins were determined by reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively.The activation of FXR ameliorated hepatocyte apoptosis, as demonstrated by TUNEL analysis and downregulation of the Fas/Fas ligand, tumor necrosis factor‑related apoptosis‑inducing ligand and caspase‑3.FXR, therefore, exerts a protective role against ConA-induced apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China.

ABSTRACT
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease associated with interface hepatitis, the presence of autoantibodies, regulatory T‑cell dysfunction and raised plasma liver enzyme levels. The present study assessed the hepatoprotective and antiapoptotic role of farnesoid X receptor (FXR) in AIH. a mouse model of AIH was induced by treatment with concanavalin A (ConA). The FXR agonist, chenodeoxycholic acid (CDCA), was administered to mice exhibiting ConA‑induced liver injury and a normal control. Blood samples were obtained to detect the levels of aminotransferases and inflammatory cytokines. Liver specimens were collected, and hematoxylin‑eosin staining was used for histopathological examination and detection. Apoptosis was evaluated using the terminal deoxynucleotidyl-transferase‑mediated dUTP nick end labeling (TUNEL) method. The expression levels of apoptosis‑associated genes and proteins were determined by reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively. The results demonstrated that FXR was downregulated at the mRNA and protein level in the liver specimens of mice induced with ConA‑induced hepatitis. Increased levels of aminotransferases and inflammatory cytokines, including interferon‑γ, tumor necrosis factor‑α, interleukin (IL)‑4 and IL‑2, were detected in ConA‑treated mice. The mice pretreated with the FXR agonist, CDCA, were more resistant to ConA hepatitis, as indicated by reduced levels of alanine transaminase/aspartate aminotransferase and aminotransferases. The activation of FXR ameliorated hepatocyte apoptosis, as demonstrated by TUNEL analysis and downregulation of the Fas/Fas ligand, tumor necrosis factor‑related apoptosis‑inducing ligand and caspase‑3. Taken together, FXR activation ameliorated liver injury and suppressed inflammatory cytokines in ConA‑induced hepatitis. FXR, therefore, exerts a protective role against ConA-induced apoptosis.

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Activation of FXR suppressed inflammatory cytokines in ConA-induced hepatitis. Serum levels of IFN-γ, TNF-α, IL-4 and IL-2 were measured in ConA-treated mice and normal controls in the presence or absence of CDCA at different time points. #P<0.05, ConA-induced hepatitis in the presence of CDCA, vs. ConA-induced hepatitis without CDCA; *P<0.05, ConA induced hepatitis without CDCA, vs. control. CDCA, chenodeoxycholic acid; ConA, conconavalin A; FXR, farnesoid receptor X; IFN-γ, interferon-γ; IL, interleukin, TNF-α, tumor necrosis factor-α; PBS, phosphate-buffered saline.
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f3-mmr-12-04-5821: Activation of FXR suppressed inflammatory cytokines in ConA-induced hepatitis. Serum levels of IFN-γ, TNF-α, IL-4 and IL-2 were measured in ConA-treated mice and normal controls in the presence or absence of CDCA at different time points. #P<0.05, ConA-induced hepatitis in the presence of CDCA, vs. ConA-induced hepatitis without CDCA; *P<0.05, ConA induced hepatitis without CDCA, vs. control. CDCA, chenodeoxycholic acid; ConA, conconavalin A; FXR, farnesoid receptor X; IFN-γ, interferon-γ; IL, interleukin, TNF-α, tumor necrosis factor-α; PBS, phosphate-buffered saline.

Mentions: To determine the effect of FXR on inflammatory responses, the serum cytokine levels of IFN-γ, TNF-α, IL-4 and IL-2 were measured. A significant increase (P<0.05) in the level of the inflammatory cytokines was identified following ConA injection, particularly in the mice fed a normal diet. The levels of these cytokines were reduced by CDCA treatment (Fig. 3).


Activated farnesoid X receptor attenuates apoptosis and liver injury in autoimmune hepatitis.

Lian F, Wang Y, Xiao Y, Wu X, Xu H, Liang L, Yang X - Mol Med Rep (2015)

Activation of FXR suppressed inflammatory cytokines in ConA-induced hepatitis. Serum levels of IFN-γ, TNF-α, IL-4 and IL-2 were measured in ConA-treated mice and normal controls in the presence or absence of CDCA at different time points. #P<0.05, ConA-induced hepatitis in the presence of CDCA, vs. ConA-induced hepatitis without CDCA; *P<0.05, ConA induced hepatitis without CDCA, vs. control. CDCA, chenodeoxycholic acid; ConA, conconavalin A; FXR, farnesoid receptor X; IFN-γ, interferon-γ; IL, interleukin, TNF-α, tumor necrosis factor-α; PBS, phosphate-buffered saline.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581797&req=5

f3-mmr-12-04-5821: Activation of FXR suppressed inflammatory cytokines in ConA-induced hepatitis. Serum levels of IFN-γ, TNF-α, IL-4 and IL-2 were measured in ConA-treated mice and normal controls in the presence or absence of CDCA at different time points. #P<0.05, ConA-induced hepatitis in the presence of CDCA, vs. ConA-induced hepatitis without CDCA; *P<0.05, ConA induced hepatitis without CDCA, vs. control. CDCA, chenodeoxycholic acid; ConA, conconavalin A; FXR, farnesoid receptor X; IFN-γ, interferon-γ; IL, interleukin, TNF-α, tumor necrosis factor-α; PBS, phosphate-buffered saline.
Mentions: To determine the effect of FXR on inflammatory responses, the serum cytokine levels of IFN-γ, TNF-α, IL-4 and IL-2 were measured. A significant increase (P<0.05) in the level of the inflammatory cytokines was identified following ConA injection, particularly in the mice fed a normal diet. The levels of these cytokines were reduced by CDCA treatment (Fig. 3).

Bottom Line: The expression levels of apoptosis‑associated genes and proteins were determined by reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively.The activation of FXR ameliorated hepatocyte apoptosis, as demonstrated by TUNEL analysis and downregulation of the Fas/Fas ligand, tumor necrosis factor‑related apoptosis‑inducing ligand and caspase‑3.FXR, therefore, exerts a protective role against ConA-induced apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China.

ABSTRACT
Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease associated with interface hepatitis, the presence of autoantibodies, regulatory T‑cell dysfunction and raised plasma liver enzyme levels. The present study assessed the hepatoprotective and antiapoptotic role of farnesoid X receptor (FXR) in AIH. a mouse model of AIH was induced by treatment with concanavalin A (ConA). The FXR agonist, chenodeoxycholic acid (CDCA), was administered to mice exhibiting ConA‑induced liver injury and a normal control. Blood samples were obtained to detect the levels of aminotransferases and inflammatory cytokines. Liver specimens were collected, and hematoxylin‑eosin staining was used for histopathological examination and detection. Apoptosis was evaluated using the terminal deoxynucleotidyl-transferase‑mediated dUTP nick end labeling (TUNEL) method. The expression levels of apoptosis‑associated genes and proteins were determined by reverse transcription‑quantitative polymerase chain reaction and western blotting, respectively. The results demonstrated that FXR was downregulated at the mRNA and protein level in the liver specimens of mice induced with ConA‑induced hepatitis. Increased levels of aminotransferases and inflammatory cytokines, including interferon‑γ, tumor necrosis factor‑α, interleukin (IL)‑4 and IL‑2, were detected in ConA‑treated mice. The mice pretreated with the FXR agonist, CDCA, were more resistant to ConA hepatitis, as indicated by reduced levels of alanine transaminase/aspartate aminotransferase and aminotransferases. The activation of FXR ameliorated hepatocyte apoptosis, as demonstrated by TUNEL analysis and downregulation of the Fas/Fas ligand, tumor necrosis factor‑related apoptosis‑inducing ligand and caspase‑3. Taken together, FXR activation ameliorated liver injury and suppressed inflammatory cytokines in ConA‑induced hepatitis. FXR, therefore, exerts a protective role against ConA-induced apoptosis.

Show MeSH
Related in: MedlinePlus