Limits...
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.

Show MeSH

Related in: MedlinePlus

The expression of FXR in ConA-induced hepatitis. (A) The mRNA expression of FXR in ConA-induced hepatitis and normal controls was detected by reverse transcription-quantitative polymerase chain reaction. (B) The protein expression of FXR in ConA-induced hepatitis and normal controls was detected by western blotting. (C) The mRNA expression of FXR in CDCA-treated hepatitis and normal controls was detected by reverse transcription-quantitative polymerase chain reaction. (D) The protein expression of FXR in CDCA-treated hepatitis and normal controls was detected by western blotting. (E) Hematoxylin-eosin staining (original magnification ×100) of paraffin-embedded liver sections of ConA-induced hepatitis and normal controls. Immunohistochemical staining (original magnification ×200) for the detection of FXR. *P<0.05, ConA-induced hepatitis vs. normal controls, and **P<0.05, C57BL/6+CDCA mice vs. C57BL/6+PBS. CDCA, chenodeoxycholic acid; ConA, concanavalin A; FXR, farnesoid receptor X; PBS, phosphate-buffered saline.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4581797&req=5

f1-mmr-12-04-5821: The expression of FXR in ConA-induced hepatitis. (A) The mRNA expression of FXR in ConA-induced hepatitis and normal controls was detected by reverse transcription-quantitative polymerase chain reaction. (B) The protein expression of FXR in ConA-induced hepatitis and normal controls was detected by western blotting. (C) The mRNA expression of FXR in CDCA-treated hepatitis and normal controls was detected by reverse transcription-quantitative polymerase chain reaction. (D) The protein expression of FXR in CDCA-treated hepatitis and normal controls was detected by western blotting. (E) Hematoxylin-eosin staining (original magnification ×100) of paraffin-embedded liver sections of ConA-induced hepatitis and normal controls. Immunohistochemical staining (original magnification ×200) for the detection of FXR. *P<0.05, ConA-induced hepatitis vs. normal controls, and **P<0.05, C57BL/6+CDCA mice vs. C57BL/6+PBS. CDCA, chenodeoxycholic acid; ConA, concanavalin A; FXR, farnesoid receptor X; PBS, phosphate-buffered saline.

Mentions: Hepatic histopathology was assessed, as indicated above. Liver injury induced by ConA injection was characterized by hepatocellular necrosis, portal inflammation, mononuclear cell infiltration into the parenchyma and sinusoidal hyperemia. The liver structures of the untreated mice were normal. Mice, which were administered CDCA alone, developed no liver injury. As shown in Fig. 1, the expression of FXR was detected in the liver of all mice. CDCA treatment increased the expression of FXR and FXR was demonstrated to be present in smaller quantities in mice inflicted with ConA-induced hepatitis (Fig. 1).


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)

The expression of FXR in ConA-induced hepatitis. (A) The mRNA expression of FXR in ConA-induced hepatitis and normal controls was detected by reverse transcription-quantitative polymerase chain reaction. (B) The protein expression of FXR in ConA-induced hepatitis and normal controls was detected by western blotting. (C) The mRNA expression of FXR in CDCA-treated hepatitis and normal controls was detected by reverse transcription-quantitative polymerase chain reaction. (D) The protein expression of FXR in CDCA-treated hepatitis and normal controls was detected by western blotting. (E) Hematoxylin-eosin staining (original magnification ×100) of paraffin-embedded liver sections of ConA-induced hepatitis and normal controls. Immunohistochemical staining (original magnification ×200) for the detection of FXR. *P<0.05, ConA-induced hepatitis vs. normal controls, and **P<0.05, C57BL/6+CDCA mice vs. C57BL/6+PBS. CDCA, chenodeoxycholic acid; ConA, concanavalin A; FXR, farnesoid receptor X; PBS, phosphate-buffered saline.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1-mmr-12-04-5821: The expression of FXR in ConA-induced hepatitis. (A) The mRNA expression of FXR in ConA-induced hepatitis and normal controls was detected by reverse transcription-quantitative polymerase chain reaction. (B) The protein expression of FXR in ConA-induced hepatitis and normal controls was detected by western blotting. (C) The mRNA expression of FXR in CDCA-treated hepatitis and normal controls was detected by reverse transcription-quantitative polymerase chain reaction. (D) The protein expression of FXR in CDCA-treated hepatitis and normal controls was detected by western blotting. (E) Hematoxylin-eosin staining (original magnification ×100) of paraffin-embedded liver sections of ConA-induced hepatitis and normal controls. Immunohistochemical staining (original magnification ×200) for the detection of FXR. *P<0.05, ConA-induced hepatitis vs. normal controls, and **P<0.05, C57BL/6+CDCA mice vs. C57BL/6+PBS. CDCA, chenodeoxycholic acid; ConA, concanavalin A; FXR, farnesoid receptor X; PBS, phosphate-buffered saline.
Mentions: Hepatic histopathology was assessed, as indicated above. Liver injury induced by ConA injection was characterized by hepatocellular necrosis, portal inflammation, mononuclear cell infiltration into the parenchyma and sinusoidal hyperemia. The liver structures of the untreated mice were normal. Mice, which were administered CDCA alone, developed no liver injury. As shown in Fig. 1, the expression of FXR was detected in the liver of all mice. CDCA treatment increased the expression of FXR and FXR was demonstrated to be present in smaller quantities in mice inflicted with ConA-induced hepatitis (Fig. 1).

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