Polyenephosphatidylcholine prevents alcoholic liver disease in PPARalpha-null mice through attenuation of increases in oxidative stress.
Polyenephosphatidylcholine prevents alcoholic liver disease in PPARalpha-null mice through attenuation of increases in oxidative stress.
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DOI：
10.1016/j.jhep.2009.01.025
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发表时间：
2009-06
影响因子：
25.7
通讯作者：
Aoyama T
中科院分区：
文献类型：
--
作者：
Okiyama W;Tanaka N;Nakajima T;Tanaka E;Kiyosawa K;Gonzalez FJ;Aoyama T
酒精性肝病（ALD）是肝硬化的主要原因之一，但缺乏有效的治疗策略。多烯磷脂酰胆碱（PPC）是必需磷脂的主要成分，可预防狒狒酒精性肝纤维化，但其确切机制尚不清楚。我们的目的是探索PPC对酒精喂养的过氧化物酶体增殖物激活受体α（Ppara）-null小鼠ALD的影响，显示出与人类ALD的几个相似之处。雄性野生型和Ppara缺失小鼠配对喂食Lieber-DeCarli对照或含4%乙醇的饲料（含或不含PPC）（30 mg/kg/天）6个月。PPC能显著改善乙醇所致的肝细胞损伤和肝硬化。这些效应可能是通过下调活性氧（ROS）生成酶（包括细胞色素P450 2 E1、酰基辅酶A氧化酶和NADPH氧化酶）以及恢复Toll样受体4和CD 14增加而降低氧化应激的结果。PPC还降低Bax和截短的Bid，从而抑制细胞凋亡。此外，PPC抑制了转化生长因子-β1表达和肝星状细胞活化的增加，从而延缓了肝纤维化的发生。PPC对ALD表现出抗炎、抗凋亡和抗纤维化作用，这是由于抑制ROS生成酶的过表达。我们的结果揭示了PPC抗氧化作用的详细分子机制。
Alcoholic liver disease (ALD) is one of the leading causes of cirrhosis and yet efficient therapeutic strategies are lacking. Polyenephospha tidylcholine (PPC), a major component of essential phospholipids, prevented alcoholic liver fibrosis in baboons, but its precise mechanism remains uncertain. We aimed to explore the effects of PPC on ALD using ethanol-fed peroxisome proliferator-activated receptor α(Ppara)-null mice, showing several similarities to human ALD. Male wild-type and Ppara-null mice were pair-fed a Lieber-DeCarli control or 4% ethanol-containing diet with or without PPC (30 mg/kg/day) for 6 months. PPC significantly ameliorated ethanol-induced hepatocyte damage and hepatitis in Ppara-nullmice. These effects were likely a consequence of decreased oxidative stress through down-regulation of reactive oxygen species (ROS)-generating enzymes, including cytochrome P450 2E1, acyl-CoA oxidase, and NADPH oxidases, in addition to restoration of increases in Toll-like receptor 4 and CD14. PPC also decreased Bax and truncated Bid, thus inhibiting apoptosis. Furthermore, PPC suppressed increases in transforming growth factor-β1 expression and hepatic stellate cell activation, which retarded hepatic fibrogenesis. PPC exhibited anti-inflammatory, anti-apoptotic, and anti-fibrotic effects on ALD as a result of inhibition of the overexpression of ROS-generating enzymes. Our results demonstrate detailed molecular mechanisms of the antioxidant action of PPC.
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影响因子：
4.8
作者：
Anrather, J;Racchumi, G;Iadecola, C
通讯作者：
Iadecola, C
影响因子：
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作者：
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影响因子：
13.5
作者：
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Nieto, Natalia
DOI：
10.1097/01.alc.0000171896.37022.f7
发表时间：
2005-07-01
影响因子：
3.2
作者：
Seitz, HK;Lieber, CS;Horie, Y
通讯作者：
Horie, Y
DOI：
10.1016/s0006-291x(02)02672-4
发表时间：
2002-12-06
影响因子：
3.1
作者：
Cao, Q;Mak, KM;Lieber, CS
通讯作者：
Lieber, CS