Oxidized low-density-lipoprotein accumulation is associated with liver fibrosis in experimental cholestasis

OBJECTIVE: The aim of the present study was to examine the probable relationship between the accumulation of oxLDL and hepatic fibrogenesis in cholestatic rats. INTRODUCTION: There is growing evidence to support the current theories on how oxidative stress that results in lipid peroxidation is involved in the pathogenesis of cholestatic liver injury and fibrogenesis. One of the major and early lipid peroxidation products, OxLDL, is thought to play complex roles in various immuno-inflammatory mechanisms. METHODS: A prolonged (21-day) experimental bile duct ligation was performed on Wistar-albino rats. Biochemical analysis of blood, histopathologic evaluation of liver, measurement of the concentration of malondialdehyde (MDA) and superoxide-dismutase (SOD) in liver tissue homogenates, and immunofluorescent staining for oxLDL in liver tissue was conducted in bile-duct ligated (n = 8) and sham-operated rats (n = 8). RESULTS: Significantly higher levels of MDA and lower concentrations of SOD were detected in jaundiced rats than in the sham-operated rats. Positive oxLDL staining was also observed in liver tissue sections of jaundiced rats. Histopathological examination demonstrated that neither fibrosis nor other indications of hepatocellular injury were found in the sham-operated group, while features of severe hepatocellular injury, particularly fibrosis, were found in jaundiced rats. CONCLUSION: Our results support the finding that either oxLDLs are produced as an intermediate agent during exacerbated oxidative stress or they otherwise contribute to the various pathomechanisms underlying the process of liver fibrosis. Whatever the mechanism, it is clear that an association exists between elevated oxLDL levels and hepatocellular injury, particularly with fibrosis. Further studies are needed to evaluate the potential effects of oxLDLs on the progression of secondary biliary cirrhosis.

Obstructive jaundice induces early depression of mitochondrial respiration in rat hepatocytes

INTRODUCTION: Oxidative phosphorylation dysfunction of hepatocyte mitochondria is involved in the pathophysiology of organ dysfunction following obstructive jaundice (OJ). However the time period from biliary occlusion to the occurrence of the dysfunction has not been determined decisively. PURPOSE: To evaluate the early effects (1 d and 7 d) of OJ on liver mitochondria respiratory function in rats. METHODS: Male Wistar rats (200-250 g) were randomly divided into the following 3 groups: laparotomy plus OJ for 24 h (1d group) (n = 10); laparotomy plus OJ for 7 d (7d group) (n = 10); sham control procedure (CTR group) (n = 12). At the end of OJ periods, total serum bilirubin level, hepatic enzyme activity levels (GOT, GTP, Gama-GT, ALP), mitochondrial respiration phases S3 and S4, as well as the respiratory control ratio (RC = S3/S4), and ADP consumption/oxygen consumption (ADP/O) ratio, were determined. RESULTS: Total serum bilirubin, activity of most hepatic enzymes, and O2 consumption during basal (S4) respiration were increased in the 1d and 7d groups (ANOVA, p = 0.05 vs. CTR). After ADP addition, the O2 consumption rate (S3) in the 1d group remained similar to the CTR rate (ANOVA p > .05), while the RC rate was reduced (ANOVA, p = 0.001) vs. CTR. The effects observed on mitochondrial respiration in the 1d group were exacerbated in the 7d group. CONCLUSION: These results indicate that OJ induces early (24 h) depression of liver mitochondria respiration, and thus may lead to early reduction in the production of high energy bonds.

INTRODUÇÃO: A disfunção da fosforilação oxidativa das mitocôndrias do hepatócito está envolvida na fisiopatologia da disfunção orgânica subseqüente à icterícia obstrutiva (IO). Entretanto, a precocidade da ocorrência desta disfunção permanece obscura. OBJETIVO: Avaliar o efeito precoce da IO na função respiratória mitocondrial em ratos. MÉTODOS: Ratos Wistar machos (200 a 250g) foram randomizados em 3 grupos que foram submetidos a laparotomia mais: IO por 24hs (grupo 1d)(n=10); IO por 7 dias (grupo 7d)(n=10; procedimento simulado (grupo CTR)(n=12). Ao final dos períodos de IO, foram determinados: bilirrubina sérica total, atividade de enzimas hepáticas (TGO, TGP, Gama-GT, FA), e as fases S3 e S4 da respiração mitocondrial, bem como o razão do controle respiratório (RC = S3/S4), e a razão entre consumo de ADP/consumo de oxigênio (ADP/O). RESULTADOS: Observou-se significativo aumento de bilirrubina sérica total, enzimas hepáticas, e consumo de O2 durante a respiração basal (S4) no grupo de IO por 24hs (ANOVA, p=0.009). Após adição de ADP, a taxa de consumo de O2 (S3) não diminuiu significativamente no grupo de IO, comparado com o CTR (ANOVA, p>0.05); entretanto, a razão do controle respiratório (RC) foi significativamente mais baixa comparada com o CTR (ANOVA, p=0.001). Os efeitos observados na respiração mitocondrial no grupo do dia 1d estavam exacerbados no grupo 7d. CONCLUSÃO: Estes resultados indicam que a icterícia obstrutiva induz depressão precoce (24hs) da respiração mitocondrial, e pode assim levar à redução da produção de ligações de alta energia.