Petr T, Smíd V, Kučerová V, Váňová K, Leníček M, Vítek L, Smíd F, Muchová L
Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
Physiol Res. 2014;63(3):359-67. doi: 10.33549/physiolres.932665. Epub 2014 Feb 24.
Cholestasis is characterized by the elevation of serum total bile acids (TBA), which leads to the production of both free radicals and oxidative stress. Although they do not share the same mechanisms, membrane glycosphingolipids (GSL) and the antioxidant enzyme heme oxygenase-1 (HMOX1) both act against the pro-oxidative effect of TBA. The aim of the study was to assess the role of HMOX on GSL redistribution and composition within hepatocytes in the rat model of estrogen-induced cholestasis. Compared to the controls, an increase of total gangliosides in the liver homogenates of the cholestatic group (P=0.001) was detected; further, it paralleled along with the activation of their biosynthetic b-branch pathway (P<0.01). These effects were partially prevented by HMOX activation. Cholestasis was accompanied by a redistribution of GM1 ganglioside from the cytoplasm to the sinusoids; while HMOX activation led to the retention of GM1 in the cytoplasm (P=0.014). Our study shows that estrogen-induced cholestasis is followed by changes in the synthesis and/or distribution of GSL. These changes are not only triggered by the detergent power of accumulated TBA, but also by their pro-oxidant action. Increases in the antioxidant defenses might represent an important supportive therapeutic measure for patients with cholestatic liver disease.
胆汁淤积的特征是血清总胆汁酸（TBA）升高，这会导致自由基产生和氧化应激。尽管膜糖鞘脂（GSL）和抗氧化酶血红素加氧酶-1（HMOX1）作用机制不同，但二者均能对抗TBA的促氧化作用。本研究旨在评估在雌激素诱导的胆汁淤积大鼠模型中，HMOX对肝细胞内GSL重新分布和组成的作用。与对照组相比，胆汁淤积组肝脏匀浆中总神经节苷脂增加（P=0.001）；此外，这与它们生物合成的b分支途径的激活平行（P<0.01）。HMOX激活可部分预防这些作用。胆汁淤积伴有GM1神经节苷脂从细胞质向窦状隙重新分布；而HMOX激活导致GM1保留在细胞质中（P=0.014）。我们的研究表明，雌激素诱导的胆汁淤积后会出现GSL合成和/或分布的变化。这些变化不仅由累积的TBA的去污力触发，还由其促氧化作用触发。增强抗氧化防御可能是胆汁淤积性肝病患者重要的支持性治疗措施。
