Brief Article
Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Sep 21, 2012; 18(35): 4934-4943
Published online Sep 21, 2012. doi: 10.3748/wjg.v18.i35.4934
Coexistence of hyperlipidemia and acute cerebral ischemia/reperfusion induces severe liver damage in a rat model
Wei-Hong Gong, Wen-Xia Zheng, Jun Wang, Shi-Hui Chen, Bo Pang, Xia-Min Hu, Xiao-Lu Cao
Wei-Hong Gong, Wen-Xia Zheng, Jun Wang, Shi-Hui Chen, Bo Pang, Xia-Min Hu, Xiao-Lu Cao, Department of Pharmacology, College of Medicine, Wuhan University of Science and Technology, Wuhan 430065, Hubei Province, China
Author contributions: Gong WH, Zheng WX, Wang J and Chen SH contributed equally to this work; Gong WH, Zheng WX, Chen SH and Hu XM designed the research; Gong WH, Zheng WX, Chen SH, Pang B and Cao XL performed the research; Gong WH, Zheng WX, Wang J and Chen SH analyzed the data and wrote the paper.
Correspondence to: Xia-Min Hu, MD, PhD, Professor, Department of Pharmacology, College of Medicine, Wuhan University of Science and Technology, Wuhan 430065, Hubei Province, China. huxiamin@wust.edu.cn
Telephone: +86-27-68893640 Fax: +86-27-68893590
Received: October 8, 2011
Revised: April 13, 2012
Accepted: May 6, 2012
Published online: September 21, 2012
Abstract

AIM: To investigate the correlation of hyperlipemia (HL) and acute cerebral ischemia/reperfusion (I/R) injury on liver damage and its mechanism.

METHODS: Rats were divided into 4 groups: control, HL, I/R and HL+I/R. After the induction of HL via a high-fat diet for 18 wk, middle cerebral artery occlusion was followed by 24 h of reperfusion to capture I/R. Serum alanine transaminase (ALT) and aspartate aminotransferase (AST) were analyzed as part of liver function tests and liver damage was further assessed by histological examination. Hepatocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. The expression of genes related to apoptosis (caspase-3, bcl-2) was assayed by immunohistochemistry and Western blotting. Serum tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1) and liver mitochondrial superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA) and Ca2+ levels were measured to determine inflammatory and oxidative/antioxidative status respectively. Microsomal hydroxylase activity of the cytochrome P450 2E1 (CYP2E1)-containing enzyme was measured with aniline as the substrate, and CYP2E1 expression in the liver tissue and microsome was determined by immunohistochemistry and Western blotting respectively.

RESULTS: HL alone induced by high-fat diet for 18 wk resulted in liver damage, indicated by histopathological analysis, and a considerable increase in serum ALT (25.13 ± 16.90 vs 9.56 ± 1.99, P < 0.01) and AST levels (18.01 ± 10.00 vs 11.33 ± 4.17, P < 0.05) compared with control. Moreover, HL alone induced hepatocyte apoptosis, which was determined by increased TUNEL-positive cells (4.47 ± 0.45 vs 1.5 ± 0.22, P < 0.01), higher caspase-3 and lower bcl-2 expression. Interestingly, compared with those in control, HL or I/R groups, massive increases of serum ALT (93.62 ± 24.00 vs 9.56 ± 1.99, 25.13 ± 16.90 or 12.93 ± 6.14, P < 0.01) and AST (82.32 ± 26.92 vs 11.33 ± 4.17, 18.01 ± 10.00 or 14.00 ± 6.19, P < 0.01) levels in HL+I/R group were observed suggesting severe liver damage, which was confirmed by liver histology. In addition, HL combined with I/R also caused significantly increased hepatocyte apoptosis, as evidenced by increased TUNEL-positive cells (6.20 ± 0.29 vs 1.5 ± 0.22, 4.47 ± 0.45 or 1.97 ± 0.47, P < 0.01), elevated expression of caspase-3 and lower expression of bcl-2. Furthermore, when compared to HL or I/R alone, HL plus I/R enhanced serum TNF-α, IL-1, liver mitochondrial MDA and Ca2+ levels, suppressed SOD and GSH-Px in liver mitochondria, and markedly up-regulated the activity (11.76 ± 2.36 vs 4.77 ± 2.31 or 3.11 ± 1.35, P < 0.01) and expression (3.24 ± 0.38 vs 1.98 ± 0.88 or 1.72 ± 0.58, P < 0.01) of CYP2E1 in liver.

CONCLUSION: The coexistence of HL and acute cerebral I/R induces severe liver damage, suggesting that cerebral ischemic stroke would exaggerate the damage of liver caused by HL. This effect is possibly due to enhanced CYP2E1 induction which further promotes oxidative damage, inflammation and hepatocyte apoptosis.

Keywords: Hyperlipidemia; High-fat diet; Cerebral ischemia/reperfusion; Liver damage; Hepatocyte apoptosis; Cytochrome P450 2E1