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

Tian-Yu Zhao,Zhi-Jun Duan,Xiao-Han Zhai,Ying Zhu,Gang Zhao,Chun-Yan Li,Li-Xia Wang,Chun-Ye Ma,Dong Yang,Li-Ping Su

doi:10.1186/s12876-015-0311-5

Abstract

BackgroundIntestinal 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.MethodsWe 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.ResultsSerum 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.ConclusionsTight 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.

Highlights

Intestinal barrier dysfunction is the consequence of liver cirrhosis, and an active participant in the development of liver cirrhosis
External administration of insulin-like growth factor 1 (IGF-1) restored IGF-1 level of liver cirrhosis and reduced the levels of serum alanine transaminase (ALT) and aspartate transaminase (AST) (Fig. 2a, b and c), which implicated that IGF-1 protected hepatocytes from damaging in liver cirrhosis
We found that IGF-1 increased the transepithelial electrical resistance (TEER) values (Fig. 3c) in Caco-2 monolayer through upregulating occludin and caludin-1 expressions (Fig. 4e, f, g and h), which indicated that IGF-1 upregulated these two tight junction proteins in intestinal cells to restore intestinal tight junctions

Summary

Introduction

Intestinal barrier dysfunction is the consequence of liver cirrhosis, and an active participant in the development of liver cirrhosis. The present study aims to investigate the mechanisms of IGF-1 improving intestinal barrier function via regulating tight junctions in intestines. All the complications are the consequences of liver dysfunction and portal hypertension. Intestinal barrier dysfunction is the consequence of portal hypertension and a risk factor for spontaneous bacterial peritonitis. It is found that intestinal barrier interruption is the consequence of liver cirrhosis, and an active participant in the development of liver damage and portal hypertension [1, 2]. Bacterial translocation and increased lipopolysaccharides (LPS) permeability through defective intestinal barrier could cause proinflammatory cytokines to be released from polymorphonuclear cells in the portal vein system. Pro-inflammatory cytokines could cause hepatocytic injury and worsen liver dysfunction in liver cirrhosis [3]

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