From fatty liver to fibrosis: A tale of "second hit"
From fatty liver to fibrosis: A tale of "second hit"
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DOI：
10.3748/wjg.v19.i8.1158
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发表时间：
2013-02-28
影响因子：
4.3
通讯作者：
Senturk, Hakan
中科院分区：
文献类型：
--
作者：
Basaranoglu, Metin;Basaranoglu, Gokcen;Senturk, Hakan
虽然对脂肪如何在肝脏中积累有很多了解，但对这如何导致持续的肝细胞损伤仍有很多未知。损伤的后果被认为是非酒精性脂肪性肝炎（NASH）和进行性纤维化。肝细胞内脂肪的积累使肝脏对各种原因造成的损伤敏感，并且脂肪肝的再生能力受损。在将脂肪的积累识别为“第一次打击”的范例中，额外的压力源有时被称为“第二次打击”。第二次打击的可能候选者包括氧化应激增加、脂质过氧化和有毒产物如丙二醛和4-羟基壬烯醛的释放、抗氧化剂、脂肪细胞因子、转化生长因子（TGF）-β、Fas配体减少、线粒体功能障碍、CYP引起的脂肪酸氧化（图2 E1、4A 10和4A 14）和过氧化物酶体、过量的铁、小肠细菌过度生长和肠源性毒素如脂多糖和乙醇的产生。氧化应激是肝细胞损伤的主要机制之一。先前的研究已经明确观察到氧化应激标志物和脂质过氧化产物的血浆和组织水平增加，肝脏和血浆抗氧化剂水平降低。也有一些间接证据表明抗氧化剂如维生素E、S-腺苷甲硫氨酸、甜菜碱、放血除铁和N-乙酰半胱氨酸在NASH中的益处。然而，NASH和氧化应激之间的因果关系或致病联系迄今尚未建立。在NASH中已经确定了活性氧产生增加的许多来源，包括促炎细胞因子如肿瘤坏死因子（TNF）-α、铁过载、超负荷和功能障碍的线粒体、CYP和过氧化物酶体。简言之，NASH的发病机制是多因素的，并且过量的细胞内脂肪酸、氧化应激、ATP耗竭和线粒体功能障碍是脂肪变性肝脏中肝细胞损伤的重要原因。(C)2013年百世登。All rights reserved.
Although much is known about how fat accumulates in the liver, much remains unknown about how this causes sustained hepatocellular injury. The consequences of injury are recognized as nonalcoholic steatohepatitis (NASH) and progressive fibrosis. The accumulation of fat within the hepatocytes sensitizes the liver to injury from a variety of causes and the regenerative capacity of a fatty liver is impaired. An additional stressor is sometimes referred to as a "second hit" in a paradigm that identifies the accumulation of fat as the "first hit". Possible candidates for the second hit include increased oxidative stress, lipid peroxidation and release of toxic products such as malondialdehyde and 4-hydroxynonenal, decreased antioxidants, adipocytokines, transforming growth factor (TGF)-beta, Fas ligand, mitochondrial dysfunction, fatty acid oxidation by CYPs (CYP 2E1, 4A10 and 4A14), and peroxisomes, excess iron, small intestinal bacterial overgrowth, and the generation of gut-derived toxins such as lipopolysaccharide and ethanol. Oxidative stress is one of the most popular proposed mechanisms of hepatocellular injury. Previous studies have specifically observed in-creased plasma and tissue levels of oxidative stress markers and lipid peroxidation products, with reduced hepatic and plasma levels of antioxidants. There is also some indirect evidence of the benefit of antioxidants such as vitamin E, S-adenosylmethionine, betaine, phlebotomy to remove iron, and N-acetylcysteine in NASH. However, a causal relationship or a pathogenic link between NASH and oxidative stress has not been established so far. A number of sources of increased reactive oxygen species production have been established in NASH that include proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha, iron overload, overburdened and dysfunctional mitochondria, CYPs, and peroxisomes. Briefly, the pathogenesis of NASH is multifactorial and excess intracellular fatty acids, oxidant stress, ATP depletion, and mitochondrial dysfunction are important causes of hepatocellular injury in the steatotic liver. (C) 2013 Baishideng. All rights reserved.