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IGF-1 decreases portal vein endotoxin via regulating intestinal tight junctions and plays a role in attenuating portal hypertension of cirrhotic rats.

Zhao TY, Su LP, Ma CY, Zhai XH, Duan ZJ, Zhu Y, Zhao G, Li CY, Wang LX, Yang D - BMC Gastroenterol (2015)

Bottom Line: LPS decreased TEER in Caco-2 cell monolayer.LPS also decreased claudin-1 and occludin expressions and increased apoptosis in Caco-2 cells.Furthermore, IGF-1 attenuated the effect of LPS on TEER, claudin-1 expression, occludin expression and apoptosis in Caco-2 cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning province, China. wwwdxycnbbs@163.com.

ABSTRACT

Background: Intestinal barrier dysfunction is not only the consequence of liver cirrhosis, but also an active participant in the development of liver cirrhosis. Previous studies showed that external administration of insulin-like growth factor 1 (IGF-1) improved intestinal barrier function in liver cirrhosis. However, the mechanism of IGF-1 on intestinal barrier in liver cirrhosis is not fully elucidated. The present study aims to investigate the mechanisms of IGF-1 improving intestinal barrier function via regulating tight junctions in intestines.

Methods: We used carbon tetrachloride induced liver cirrhotic rats to investigate the effect of IGF-1 on intestinal claudin-1 and occludin expressions, serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, severity of liver fibrosis, portal pressures, enterocytic apoptosis and lipopolysaccharides (LPS) levels in portal vein. The changes of IGF-1 in serum during the development of rat liver cirrhosis were also evaluated. Additionally, we assessed the effect of IGF-1 on claudin-1 and occludin expressions, changes of transepithelial electrical resistance (TEER) and apoptosis in Caco-2 cells to confirm in vivo findings.

Results: Serum IGF-1 levels were decreased in the development of rat liver cirrhosis, and external administration of IGF-1 restored serum IGF-1 levels. External administration of IGF-1 reduced serum ALT and AST levels, severity of liver fibrosis, LPS levels in portal vein, enterocytic apoptosis and portal pressure in cirrhotic rats. External administration of IGF-1 increased the expressions of claudin-1 and occludin in enterocytes, and attenuated tight junction dysfunction in intestines of cirrhotic rats. LPS decreased TEER in Caco-2 cell monolayer. LPS also decreased claudin-1 and occludin expressions and increased apoptosis in Caco-2 cells. Furthermore, IGF-1 attenuated the effect of LPS on TEER, claudin-1 expression, occludin expression and apoptosis in Caco-2 cells.

Conclusions: Tight junction dysfunction develops during the development of liver cirrhosis, and endotoxemia will develop subsequently. Correspondingly, increased endotoxin in portal system worsens tight junction dysfunction via decreasing intestinal occludin and claudin-1 expressions and increasing enterocytic apoptosis. Endotoxemia and intestinal barrier dysfunction form a vicious circle. External administration of IGF-1 breaks this vicious circle. Improvement of tight junctions might be one possible mechanism of the restoration of intestinal barrier function mediated by IGF-1.

No MeSH data available.


Related in: MedlinePlus

a and b Bax was increased and Bcl-2 was decreased in intestines during the development of liver cirrhosis in rats, and administration of IGF-1 attenuated Bax and Bcl-2 changes in intestines of liver cirrhosis rats. c and d Administration of LPS to Caco-2 cells decreased Bax level and increased Bcl-2 level, and IGF-1 attenuated the effect of LPS on Bax and Bcl-2 expressions in Caco-2 cells. Data were shown with the mean ± SD. **P <0.001 vs. control group, ## P <0.001 vs. CCL4 group or LPS group
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Fig6: a and b Bax was increased and Bcl-2 was decreased in intestines during the development of liver cirrhosis in rats, and administration of IGF-1 attenuated Bax and Bcl-2 changes in intestines of liver cirrhosis rats. c and d Administration of LPS to Caco-2 cells decreased Bax level and increased Bcl-2 level, and IGF-1 attenuated the effect of LPS on Bax and Bcl-2 expressions in Caco-2 cells. Data were shown with the mean ± SD. **P <0.001 vs. control group, ## P <0.001 vs. CCL4 group or LPS group

Mentions: We also postulated that high endotoxin levels in portal veins increased enterocytic apoptosis, and increased enterocytic apoptosis caused intestinal tight junction damages subsequently. TUNEL assay was used to evaluate apoptosis in vitro and in vivo. As expected, apoptosis of enterocytes was increased during the development of liver cirrhosis (Fig. 5a and b) via regulating Bax and Bcl-2 (Fig. 6a and b), and external administration of IGF-1 reduced enterocytic apoptosis in liver cirrhotic rats (Fig. 5b and c) through regulating Bax and Bcl-2 (Fig. 6a and b). In vitro experiment with Caco-2 cells proved that LPS promoted apoptosis via Bax and Bcl-2, and IGF-1 attenuated the LPS induced apoptosis through regulating Bax and Bcl-2 (Fig. 6c and d). So IGF-1 improved intestinal barrier function through attenuating apoptosis of enterocytes.Fig. 5


IGF-1 decreases portal vein endotoxin via regulating intestinal tight junctions and plays a role in attenuating portal hypertension of cirrhotic rats.

Zhao TY, Su LP, Ma CY, Zhai XH, Duan ZJ, Zhu Y, Zhao G, Li CY, Wang LX, Yang D - BMC Gastroenterol (2015)

a and b Bax was increased and Bcl-2 was decreased in intestines during the development of liver cirrhosis in rats, and administration of IGF-1 attenuated Bax and Bcl-2 changes in intestines of liver cirrhosis rats. c and d Administration of LPS to Caco-2 cells decreased Bax level and increased Bcl-2 level, and IGF-1 attenuated the effect of LPS on Bax and Bcl-2 expressions in Caco-2 cells. Data were shown with the mean ± SD. **P <0.001 vs. control group, ## P <0.001 vs. CCL4 group or LPS group
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4495682&req=5

Fig6: a and b Bax was increased and Bcl-2 was decreased in intestines during the development of liver cirrhosis in rats, and administration of IGF-1 attenuated Bax and Bcl-2 changes in intestines of liver cirrhosis rats. c and d Administration of LPS to Caco-2 cells decreased Bax level and increased Bcl-2 level, and IGF-1 attenuated the effect of LPS on Bax and Bcl-2 expressions in Caco-2 cells. Data were shown with the mean ± SD. **P <0.001 vs. control group, ## P <0.001 vs. CCL4 group or LPS group
Mentions: We also postulated that high endotoxin levels in portal veins increased enterocytic apoptosis, and increased enterocytic apoptosis caused intestinal tight junction damages subsequently. TUNEL assay was used to evaluate apoptosis in vitro and in vivo. As expected, apoptosis of enterocytes was increased during the development of liver cirrhosis (Fig. 5a and b) via regulating Bax and Bcl-2 (Fig. 6a and b), and external administration of IGF-1 reduced enterocytic apoptosis in liver cirrhotic rats (Fig. 5b and c) through regulating Bax and Bcl-2 (Fig. 6a and b). In vitro experiment with Caco-2 cells proved that LPS promoted apoptosis via Bax and Bcl-2, and IGF-1 attenuated the LPS induced apoptosis through regulating Bax and Bcl-2 (Fig. 6c and d). So IGF-1 improved intestinal barrier function through attenuating apoptosis of enterocytes.Fig. 5

Bottom Line: LPS decreased TEER in Caco-2 cell monolayer.LPS also decreased claudin-1 and occludin expressions and increased apoptosis in Caco-2 cells.Furthermore, IGF-1 attenuated the effect of LPS on TEER, claudin-1 expression, occludin expression and apoptosis in Caco-2 cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology, The First Affiliated Hospital of Dalian Medical University, 116000, Dalian, Liaoning province, China. wwwdxycnbbs@163.com.

ABSTRACT

Background: Intestinal barrier dysfunction is not only the consequence of liver cirrhosis, but also an active participant in the development of liver cirrhosis. Previous studies showed that external administration of insulin-like growth factor 1 (IGF-1) improved intestinal barrier function in liver cirrhosis. However, the mechanism of IGF-1 on intestinal barrier in liver cirrhosis is not fully elucidated. The present study aims to investigate the mechanisms of IGF-1 improving intestinal barrier function via regulating tight junctions in intestines.

Methods: We used carbon tetrachloride induced liver cirrhotic rats to investigate the effect of IGF-1 on intestinal claudin-1 and occludin expressions, serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, severity of liver fibrosis, portal pressures, enterocytic apoptosis and lipopolysaccharides (LPS) levels in portal vein. The changes of IGF-1 in serum during the development of rat liver cirrhosis were also evaluated. Additionally, we assessed the effect of IGF-1 on claudin-1 and occludin expressions, changes of transepithelial electrical resistance (TEER) and apoptosis in Caco-2 cells to confirm in vivo findings.

Results: Serum IGF-1 levels were decreased in the development of rat liver cirrhosis, and external administration of IGF-1 restored serum IGF-1 levels. External administration of IGF-1 reduced serum ALT and AST levels, severity of liver fibrosis, LPS levels in portal vein, enterocytic apoptosis and portal pressure in cirrhotic rats. External administration of IGF-1 increased the expressions of claudin-1 and occludin in enterocytes, and attenuated tight junction dysfunction in intestines of cirrhotic rats. LPS decreased TEER in Caco-2 cell monolayer. LPS also decreased claudin-1 and occludin expressions and increased apoptosis in Caco-2 cells. Furthermore, IGF-1 attenuated the effect of LPS on TEER, claudin-1 expression, occludin expression and apoptosis in Caco-2 cells.

Conclusions: Tight junction dysfunction develops during the development of liver cirrhosis, and endotoxemia will develop subsequently. Correspondingly, increased endotoxin in portal system worsens tight junction dysfunction via decreasing intestinal occludin and claudin-1 expressions and increasing enterocytic apoptosis. Endotoxemia and intestinal barrier dysfunction form a vicious circle. External administration of IGF-1 breaks this vicious circle. Improvement of tight junctions might be one possible mechanism of the restoration of intestinal barrier function mediated by IGF-1.

No MeSH data available.


Related in: MedlinePlus