Prevention of hepatic fibrosis in a murine model of metabolic syndrome with nonalcoholic steatohepatitis
Prevention of hepatic fibrosis in a murine model of metabolic syndrome with nonalcoholic steatohepatitis
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DOI：
10.2353/ajpath.2008.070720
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发表时间：
2008-10-01
影响因子：
6
通讯作者：
McCuskey, Robert S.
中科院分区：
文献类型：
--
作者：
DeLeve, Laurie D.;Wang, Xiangdong;McCuskey, Robert S.
内源性大麻素途径在调节食欲和体重、肝脏脂质代谢和纤维化中起重要作用。用SR 141716阻断内源性大麻素受体CBI可促进体重减轻，减少肝细胞脂肪酸合成，并具有抗纤维化作用。D-4F是一种具有抗氧化特性的载脂蛋白A-1模拟物，目前正在进行治疗动脉粥样硬化的临床试验。对C57 BL/6 J小鼠饲喂高脂肪饲料7个月，然后用SR 141716或D-417处理2.5个月。SR 141716显著改善了体重、肝脏重量、血清转氨酶、胰岛素抵抗、高血糖症、高胆固醇血症、高瘦素血症和氧化应激，并显著预防了纤维化进展。D-4F改善了高胆固醇血症和高瘦素血症，而没有改善体重、脂肪性肝炎、胰岛素抵抗或氧化应激，但显著预防了纤维化。D-4F阻止体外培养诱导的星状细胞活化。总之，给予高脂肪饮食的C57 BL/6 J小鼠发展出代谢综合征的特征，伴有非酒精性脂肪性肝炎和纤维化。SR 141716和D-417均可预防脂肪性肝炎发作后的纤维化进展，即与常见临床情况相当的情况，D-4F似乎具有更普遍的抗纤维化作用。因此，任何一种化合物都有可能具有临床益处。
The endocannabinoid pathway plays an important role in the regulation of appetite and body weight, hepatic lipid metabolism, and fibrosis. Blockade of the endocannabinoid receptor CBI with SR141716 promotes weight loss, reduces hepatocyte fatty acid synthesis, and is antifibrotic. D-4F, an apolipoprotein A-1 mimetic with antioxidant properties, is currently in clinical trials for the treatment of atherosclerosis. C57BL/6J mice were fed a high-fat diet for 7 months, followed by a 2.5-month treatment with either SR141716 or D-417. SR141716 markedly improved body weight, liver weight, serum transaminases, insulin resistance, hyperglycemia, hypercholesterolemia, hyerleptinemia, and oxidative stress, accompanied by the significant prevention of fibrosis progression. D-4F improved hypercholesterolemia and hyperleptinemia without improvement in body weight, steatohepatitis, insulin resistance, or oxidative stress, and yet, there was significant prevention of fibrosis. D-4F prevented culture-induced activation of stellate cells in vitro. In summary, C57BL/6J mice given a high-fat diet developed features of metabolic syndrome with nonalcoholic steatohepatitis and fibrosis. Both SR141716 and D-417 prevented progression of fibrosis after onset of steatohepatitis, ie, a situation comparable to a common clinical scenario, with D-4F seeming to have a more general antifibrotic effect. Either compound therefore has the potential to be of clinical benefit.