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Pentoxifylline alleviates high-fat diet-induced non-alcoholic steatohepatitis and early atherosclerosis in rats by inhibiting AGE and RAGE expression.

Wu J, Zhao MY, Zheng H, Zhang H, Jiang Y - Acta Pharmacol. Sin. (2010)

Bottom Line: Serum aspartic aminotransferase (AST) and blood levels of glucose (GLU) were reduced in the PTX group relative to the NASH group.The IMT of the aorta and carotid artery was increased in the NASH group compared with the control group.PTX showed protective effects on hepatic and arterial function, partially through inhibition of AGE and RAGE expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathophysiology, Capital Medical University, Beijing, China.

ABSTRACT

Aim: To investigate the expression of advanced glycation end products (AGEs) and their receptor RAGE in the livers and blood vessels of rats with non-alcoholic steatohepatitis (NASH) and the effect of pentoxifylline (PTX) on liver and artery function in rats with NASH.

Methods: Sprague-Dawley rats were fed a high-fat diet for 12 weeks and given PTX by gavage for 4 weeks. The effects of PTX on hepatic liver and vessel function as well as the expression of AGE and RAGE in rats with NASH were assessed. The intima-media thickness (IMT) of the aorta and carotid artery was evaluated using ultrasonography.

Results: Serum aspartic aminotransferase (AST) and blood levels of glucose (GLU) were reduced in the PTX group relative to the NASH group. The IMT of the aorta and carotid artery was increased in the NASH group compared with the control group. The IMT was reduced in NASH rats after treatment with PTX. Rats with NASH demonstrated higher AGE and RAGE protein levels in the liver and arteries compared with those of control rats. PTX treatment in NASH rats resulted in a decrease in AGE and RAGE protein levels in the liver and arteries compared with those in the NASH group.

Conclusion: Early atherosclerosis was observed in rats with NASH induced by a 16-week high-fat diet. High expression of AGE and RAGE in the livers and arteries of rats with NASH may contribute to the pathogenesis of NASH and early atherosclerosis. PTX showed protective effects on hepatic and arterial function, partially through inhibition of AGE and RAGE expression.

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AGE and RAGE protein levels in the livers and arteries of rats. (A) AGE protein levels in the livers and aortas of rats were analyzed by Western blotting with the use of anti-AGE monoclonal antibody. Liver and artery protein from rats fed a normal diet (Control group), a high-fat diet (NASH group) or a high-fat diet+pentoxifylline (PTX group) for 16 weeks were isolated as described in the “Materials and methods” section. Protein samples were loaded onto 12% separating gels; the band associated with AGE displays molecular weight fragments between 25 and 30 kDa. (B) Quantitative analyses of AGE protein levels in the livers and arteries of rats. (C) RAGE protein levels in the livers and aortas of rats were analyzed by Western blotting analyses with the use of anti-RAGE monoclonal antibody. Protein samples were loaded onto 10% separating gels. Two variants of RAGE were detected: 55 kDa and 46 kDa. (D) Quantitative analyses of RAGE protein levels in the livers and arteries of rats. Data are means±SD for 10 rats per group. cP<0.05 vs the control group; fP<0.05 vs the NASH group.
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fig4: AGE and RAGE protein levels in the livers and arteries of rats. (A) AGE protein levels in the livers and aortas of rats were analyzed by Western blotting with the use of anti-AGE monoclonal antibody. Liver and artery protein from rats fed a normal diet (Control group), a high-fat diet (NASH group) or a high-fat diet+pentoxifylline (PTX group) for 16 weeks were isolated as described in the “Materials and methods” section. Protein samples were loaded onto 12% separating gels; the band associated with AGE displays molecular weight fragments between 25 and 30 kDa. (B) Quantitative analyses of AGE protein levels in the livers and arteries of rats. (C) RAGE protein levels in the livers and aortas of rats were analyzed by Western blotting analyses with the use of anti-RAGE monoclonal antibody. Protein samples were loaded onto 10% separating gels. Two variants of RAGE were detected: 55 kDa and 46 kDa. (D) Quantitative analyses of RAGE protein levels in the livers and arteries of rats. Data are means±SD for 10 rats per group. cP<0.05 vs the control group; fP<0.05 vs the NASH group.

Mentions: To confirmation AGE-RAGE pathways associated with the pathogenesis of NASH, the expression of AGE and RAGE in the livers and aortas of rats with NASH was studied. Western blotting and RT-PCR were carried out to quantify the protein and gene expression of RAGE in these tissues. AGE and RAGE protein expression in the liver was significantly induced after administration of a high-fat diet. This induction was significantly inhibited by the administration of PTX. In the aorta, AGE and RAGE protein expression was also increased in the NASH group compared with that in the control group. However, there was also a significant decrease in AGE and RAGE protein levels in the PTX group relative to the NASH group (Figure 4), but little difference was observed in hepatic and vascular RAGE mRNA levels among the three groups (data not shown).


Pentoxifylline alleviates high-fat diet-induced non-alcoholic steatohepatitis and early atherosclerosis in rats by inhibiting AGE and RAGE expression.

Wu J, Zhao MY, Zheng H, Zhang H, Jiang Y - Acta Pharmacol. Sin. (2010)

AGE and RAGE protein levels in the livers and arteries of rats. (A) AGE protein levels in the livers and aortas of rats were analyzed by Western blotting with the use of anti-AGE monoclonal antibody. Liver and artery protein from rats fed a normal diet (Control group), a high-fat diet (NASH group) or a high-fat diet+pentoxifylline (PTX group) for 16 weeks were isolated as described in the “Materials and methods” section. Protein samples were loaded onto 12% separating gels; the band associated with AGE displays molecular weight fragments between 25 and 30 kDa. (B) Quantitative analyses of AGE protein levels in the livers and arteries of rats. (C) RAGE protein levels in the livers and aortas of rats were analyzed by Western blotting analyses with the use of anti-RAGE monoclonal antibody. Protein samples were loaded onto 10% separating gels. Two variants of RAGE were detected: 55 kDa and 46 kDa. (D) Quantitative analyses of RAGE protein levels in the livers and arteries of rats. Data are means±SD for 10 rats per group. cP<0.05 vs the control group; fP<0.05 vs the NASH group.
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fig4: AGE and RAGE protein levels in the livers and arteries of rats. (A) AGE protein levels in the livers and aortas of rats were analyzed by Western blotting with the use of anti-AGE monoclonal antibody. Liver and artery protein from rats fed a normal diet (Control group), a high-fat diet (NASH group) or a high-fat diet+pentoxifylline (PTX group) for 16 weeks were isolated as described in the “Materials and methods” section. Protein samples were loaded onto 12% separating gels; the band associated with AGE displays molecular weight fragments between 25 and 30 kDa. (B) Quantitative analyses of AGE protein levels in the livers and arteries of rats. (C) RAGE protein levels in the livers and aortas of rats were analyzed by Western blotting analyses with the use of anti-RAGE monoclonal antibody. Protein samples were loaded onto 10% separating gels. Two variants of RAGE were detected: 55 kDa and 46 kDa. (D) Quantitative analyses of RAGE protein levels in the livers and arteries of rats. Data are means±SD for 10 rats per group. cP<0.05 vs the control group; fP<0.05 vs the NASH group.
Mentions: To confirmation AGE-RAGE pathways associated with the pathogenesis of NASH, the expression of AGE and RAGE in the livers and aortas of rats with NASH was studied. Western blotting and RT-PCR were carried out to quantify the protein and gene expression of RAGE in these tissues. AGE and RAGE protein expression in the liver was significantly induced after administration of a high-fat diet. This induction was significantly inhibited by the administration of PTX. In the aorta, AGE and RAGE protein expression was also increased in the NASH group compared with that in the control group. However, there was also a significant decrease in AGE and RAGE protein levels in the PTX group relative to the NASH group (Figure 4), but little difference was observed in hepatic and vascular RAGE mRNA levels among the three groups (data not shown).

Bottom Line: Serum aspartic aminotransferase (AST) and blood levels of glucose (GLU) were reduced in the PTX group relative to the NASH group.The IMT of the aorta and carotid artery was increased in the NASH group compared with the control group.PTX showed protective effects on hepatic and arterial function, partially through inhibition of AGE and RAGE expression.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathophysiology, Capital Medical University, Beijing, China.

ABSTRACT

Aim: To investigate the expression of advanced glycation end products (AGEs) and their receptor RAGE in the livers and blood vessels of rats with non-alcoholic steatohepatitis (NASH) and the effect of pentoxifylline (PTX) on liver and artery function in rats with NASH.

Methods: Sprague-Dawley rats were fed a high-fat diet for 12 weeks and given PTX by gavage for 4 weeks. The effects of PTX on hepatic liver and vessel function as well as the expression of AGE and RAGE in rats with NASH were assessed. The intima-media thickness (IMT) of the aorta and carotid artery was evaluated using ultrasonography.

Results: Serum aspartic aminotransferase (AST) and blood levels of glucose (GLU) were reduced in the PTX group relative to the NASH group. The IMT of the aorta and carotid artery was increased in the NASH group compared with the control group. The IMT was reduced in NASH rats after treatment with PTX. Rats with NASH demonstrated higher AGE and RAGE protein levels in the liver and arteries compared with those of control rats. PTX treatment in NASH rats resulted in a decrease in AGE and RAGE protein levels in the liver and arteries compared with those in the NASH group.

Conclusion: Early atherosclerosis was observed in rats with NASH induced by a 16-week high-fat diet. High expression of AGE and RAGE in the livers and arteries of rats with NASH may contribute to the pathogenesis of NASH and early atherosclerosis. PTX showed protective effects on hepatic and arterial function, partially through inhibition of AGE and RAGE expression.

Show MeSH
Related in: MedlinePlus