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Hepatocyte apoptosis is enhanced after ischemia/reperfusion in the steatotic liver.

Suzuki T, Yoshidome H, Kimura F, Shimizu H, Ohtsuka M, Takeuchi D, Kato A, Furukawa K, Yoshitomi H, Iida A, Dochi T, Miyazaki M - J Clin Biochem Nutr (2011)

Bottom Line: Liver steatosis is associated with organ dysfunction after hepatic resection and transplantation which may be caused by hepatic ischemia/reperfusion injury.In mice treated with aminoguanidine, ischemia/reperfusion-induced increases in serum alanine aminotransferase levels and apoptosis were significantly reduced in steatotic liver compared with mice treated with phosphate buffered saline.Survival of mice with steatotic livers significantly improved by treatment with aminoguanidine.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo-ku, Chiba 260-0856, Japan.

ABSTRACT
Liver steatosis is associated with organ dysfunction after hepatic resection and transplantation which may be caused by hepatic ischemia/reperfusion injury. The aim of the current study was to determine the precise mechanism leading to hepatocyte apoptosis after steatotic liver ischemia/reperfusion. Using a murine model of partial hepatic ischemia for 90 min, we examined the levels and pathway of apoptosis, and the peroxynitrite expression, serum alanine aminotransferase levels, and liver histology 1 and 4 h after reperfusion. In the steatotic liver, the peroxynitrite expression increased after ischemia/reperfusion. Significant hepatocyte apoptosis in the steatotic liver was seen after reperfusion, caused by upregulation of cleaved caspases 9 and 3, but not caspase 8. Serum alanine aminotransferase levels were elevated and histological examination revealed severe liver injury in the steatotic liver 4 h after reperfusion. In mice treated with aminoguanidine, ischemia/reperfusion-induced increases in serum alanine aminotransferase levels and apoptosis were significantly reduced in steatotic liver compared with mice treated with phosphate buffered saline. Survival of mice with steatotic livers significantly improved by treatment with aminoguanidine. Our data suggested that the steatotic liver is vulnerable to hepatic ischemia/reperfusion, leading to significant hepatocyte apoptosis by the mitochondrial permeability transition, and thereby resulting in organ dysfunction.

No MeSH data available.


Related in: MedlinePlus

Time course of hepatocyte apoptosis after reperfusion was assessed using the TUNEL method. Samples were obtained from WT (A) and FL (B) mice prior to the operation, at 1 and 4 h after reperfusion in WT (C) and FL (D) mice. Original magnification ×400. The number of apoptotic cell was quantitated to yield the apoptotic index (E). I/R: ischemia for 90 min and reperfusion. The values represent the mean ± SEM with n = 6 per group. *p<0.05, compared to the WT group.
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Figure 1: Time course of hepatocyte apoptosis after reperfusion was assessed using the TUNEL method. Samples were obtained from WT (A) and FL (B) mice prior to the operation, at 1 and 4 h after reperfusion in WT (C) and FL (D) mice. Original magnification ×400. The number of apoptotic cell was quantitated to yield the apoptotic index (E). I/R: ischemia for 90 min and reperfusion. The values represent the mean ± SEM with n = 6 per group. *p<0.05, compared to the WT group.

Mentions: TUNEL staining was performed to investigate whether hepatocyte apoptosis was induced after reperfusion. The number of TUNEL-positive apoptotic hepatocytes quantified by calculating the apoptotic index in FL mice increased significantly compared with that in sham mice 1 h after reperfusion (n = 6, respectively). This increase was not observed in WT mice. A significant increase in TUNEL-positive apoptotic cells in FL mice was seen relative to WT mice 1 and 4 h after reperfusion (Fig. 1). To determine the precise apoptosis pathway activated during ischemia/reperfusion, we performed western blot analysis of precursor and cleaved caspases-3, -8, and -9. In FL mice, cleavage of caspase-3 and -9 was increased more than that in WT mice 1 and 4 h after reperfusion. However, the expression of cleaved caspase-8 did not differ between the FL and WT mice (Fig. 2).


Hepatocyte apoptosis is enhanced after ischemia/reperfusion in the steatotic liver.

Suzuki T, Yoshidome H, Kimura F, Shimizu H, Ohtsuka M, Takeuchi D, Kato A, Furukawa K, Yoshitomi H, Iida A, Dochi T, Miyazaki M - J Clin Biochem Nutr (2011)

Time course of hepatocyte apoptosis after reperfusion was assessed using the TUNEL method. Samples were obtained from WT (A) and FL (B) mice prior to the operation, at 1 and 4 h after reperfusion in WT (C) and FL (D) mice. Original magnification ×400. The number of apoptotic cell was quantitated to yield the apoptotic index (E). I/R: ischemia for 90 min and reperfusion. The values represent the mean ± SEM with n = 6 per group. *p<0.05, compared to the WT group.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3045687&req=5

Figure 1: Time course of hepatocyte apoptosis after reperfusion was assessed using the TUNEL method. Samples were obtained from WT (A) and FL (B) mice prior to the operation, at 1 and 4 h after reperfusion in WT (C) and FL (D) mice. Original magnification ×400. The number of apoptotic cell was quantitated to yield the apoptotic index (E). I/R: ischemia for 90 min and reperfusion. The values represent the mean ± SEM with n = 6 per group. *p<0.05, compared to the WT group.
Mentions: TUNEL staining was performed to investigate whether hepatocyte apoptosis was induced after reperfusion. The number of TUNEL-positive apoptotic hepatocytes quantified by calculating the apoptotic index in FL mice increased significantly compared with that in sham mice 1 h after reperfusion (n = 6, respectively). This increase was not observed in WT mice. A significant increase in TUNEL-positive apoptotic cells in FL mice was seen relative to WT mice 1 and 4 h after reperfusion (Fig. 1). To determine the precise apoptosis pathway activated during ischemia/reperfusion, we performed western blot analysis of precursor and cleaved caspases-3, -8, and -9. In FL mice, cleavage of caspase-3 and -9 was increased more than that in WT mice 1 and 4 h after reperfusion. However, the expression of cleaved caspase-8 did not differ between the FL and WT mice (Fig. 2).

Bottom Line: Liver steatosis is associated with organ dysfunction after hepatic resection and transplantation which may be caused by hepatic ischemia/reperfusion injury.In mice treated with aminoguanidine, ischemia/reperfusion-induced increases in serum alanine aminotransferase levels and apoptosis were significantly reduced in steatotic liver compared with mice treated with phosphate buffered saline.Survival of mice with steatotic livers significantly improved by treatment with aminoguanidine.

View Article: PubMed Central - PubMed

Affiliation: Department of General Surgery, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo-ku, Chiba 260-0856, Japan.

ABSTRACT
Liver steatosis is associated with organ dysfunction after hepatic resection and transplantation which may be caused by hepatic ischemia/reperfusion injury. The aim of the current study was to determine the precise mechanism leading to hepatocyte apoptosis after steatotic liver ischemia/reperfusion. Using a murine model of partial hepatic ischemia for 90 min, we examined the levels and pathway of apoptosis, and the peroxynitrite expression, serum alanine aminotransferase levels, and liver histology 1 and 4 h after reperfusion. In the steatotic liver, the peroxynitrite expression increased after ischemia/reperfusion. Significant hepatocyte apoptosis in the steatotic liver was seen after reperfusion, caused by upregulation of cleaved caspases 9 and 3, but not caspase 8. Serum alanine aminotransferase levels were elevated and histological examination revealed severe liver injury in the steatotic liver 4 h after reperfusion. In mice treated with aminoguanidine, ischemia/reperfusion-induced increases in serum alanine aminotransferase levels and apoptosis were significantly reduced in steatotic liver compared with mice treated with phosphate buffered saline. Survival of mice with steatotic livers significantly improved by treatment with aminoguanidine. Our data suggested that the steatotic liver is vulnerable to hepatic ischemia/reperfusion, leading to significant hepatocyte apoptosis by the mitochondrial permeability transition, and thereby resulting in organ dysfunction.

No MeSH data available.


Related in: MedlinePlus