Coexistence of hyperlipidemia and acute cerebral ischemia/ reperfusion induces severe liver damage in a rat model

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 occlu- sion 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 expres- sion of genes related to apoptosis （caspase-3, bcl-2） was assayed by immunohistochemistry and Western blotting. Serum tumor necrosis factor-α （TNF-α）, in- terleukin-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 en- zyme 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 histopathologi- cal 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） com- pared with control. Moreover, HL alone induced hepato- cyte apoptosis, which was determined by increased TU- NEL-positive cells （4.47 ± 0.45 vs 1.5 ± 0.22, P 〈 0.01）, higher caspase-3 and lower bcl-2 expression. Interest- ingly, 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 com- pared to HL or I/R alone, HL plus I/R enhanced serum T