Stärkel Peter, Sempoux Christine, Leclercq Isabelle, Herin Michel, Deby C, Desager Jean-Pierre, Horsmans Yves
Laboratory of Gastroenterology, St. Luc University Hospital, Université Catholique de Louvain, Avenue Hippocrate 10, 1200 Brussels, Belgium.
J Hepatol. 2003 Oct;39(4):538-46. doi: 10.1016/s0168-8278(03)00360-x.
BACKGROUND/AIMS: Pathogenesis of non-alcoholic steatohepatitis (NASH) remains poorly understood. Cytochrome P450 2E1 (CYP 2E1), cytokines, oxidative stress and activation of hepatic stellate cells seem to play a role in this process. The aim was to determine the potential implication of these factors in the progression from uncomplicated steatosis to steatohepatitis with progressive fibrosis.
Animals were fed a standard diet, a 5% orotic acid-diet (OA) developing hepatic steatosis, or the methionine-choline deficient (MCD) diet inducing steatohepatitis for 2 and 6 weeks. Lipid peroxidation, CYP 2E1 expression and activity, expression of UCP-2, interleukin (IL)-6, transforming growth factor (TGF)beta1, KLF6 mRNAs, and activation of hepatic stellate cells were examined by gas chromatography, high-performance liquid chromatography, Western blotting, quantitative polymerase chain reaction and immunohistochemistry.
Lipid peroxidation increased in the MCD model whereas only minor changes occurred in the OA model. KLF6 and TGFbeta1 mRNAs were selectively up-regulated in MCD animals. Stellate cell activation, inflammation and collagen deposition only occurred in the MCD group. CYP 2E1 expression and activity increased in the OA group while both decreased in MCD animals. UCP-2 and IL-6 mRNA increased in both groups.
In the context of steatosis, lipid peroxidation is associated with inflammation and stellate cell activation with concomitant increase in TGFbeta1 production, possibly through up-regulation of KLF6.
背景/目的：非酒精性脂肪性肝炎（NASH）的发病机制仍未完全明确。细胞色素P450 2E1（CYP 2E1）、细胞因子、氧化应激以及肝星状细胞的激活似乎在这一过程中发挥作用。本研究旨在确定这些因素在单纯性脂肪变性进展为伴有进行性纤维化的脂肪性肝炎过程中的潜在影响。
给动物喂食标准饮食、可导致肝脂肪变性的5%乳清酸饮食（OA）或诱导脂肪性肝炎的蛋氨酸-胆碱缺乏（MCD）饮食，持续2周和6周。通过气相色谱法、高效液相色谱法、蛋白质印迹法、定量聚合酶链反应和免疫组织化学法检测脂质过氧化、CYP 2E1的表达和活性、解偶联蛋白2（UCP-2）、白细胞介素（IL）-6、转化生长因子（TGF）β1、KLF6 mRNA的表达以及肝星状细胞的激活情况。
MCD模型中脂质过氧化增加，而OA模型中仅有轻微变化。KLF6和TGFβ1 mRNA在MCD组动物中选择性上调。星状细胞激活、炎症和胶原沉积仅发生在MCD组。OA组中CYP 2E1的表达和活性增加，而在MCD组动物中两者均降低。两组中UCP-2和IL-6 mRNA均增加。
在脂肪变性的情况下，脂质过氧化与炎症和星状细胞激活相关，同时TGFβ1产生增加，可能是通过KLF6的上调实现的。
