Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis
Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis
复制标题
DOI：
10.1016/j.alcohol.2004.07.008
复制
发表时间：
2004-08-01
期刊：
影响因子：
2.3
通讯作者：
Lieber, CS
中科院分区：
文献类型：
--
作者：
Lieber, CS
酗酒者的肝病不仅是由于营养不良，而且还与乙醇的肝毒性有关，该毒性与其通过乙醇脱氢酶和细胞色素 P450 2E1 (CYP2E1) 途径的代谢以及由此产生的有毒乙醛有关。此外，乙醇脱氢酶介导的乙醇代谢产生还原形式的烟酰胺腺嘌呤二核苷（NADH），其通过刺激脂肪酸的合成并对抗脂肪酸的氧化来促进脂肪变性。过量的膳食脂质也会促进脂肪变性，并且可以通过用中链甘油三酯替代来减轻脂肪变性。通过减少丙酮酸，升高的 NADH 也会增加乳酸，从而刺激肌成纤维细胞中的胶原蛋白合成。此外，CYP2E1 活性可由其底物诱导，不仅包括乙醇，还包括脂肪酸。它们的过量和通过该途径的代谢产生自由基的释放，从而引起氧化应激、脂质过氧化和膜损伤，包括酶活性改变。脂质过氧化产物（例如 4-羟基壬烯醛）刺激胶原蛋白生成和纤维化，由于乙醛与肝星状细胞中原胶原的羧基末端前肽形成加合物，因此胶原蛋白合成的反馈抑制减弱，从而进一步增加胶原蛋白生成和纤维化。乙醛对线粒体也有毒，它通过与还原型谷胱甘肽结合并促进其泄漏而加剧线粒体的氧化应激。氧化应激和相关的细胞损伤会促进炎症，而库普弗细胞中促炎细胞因子肿瘤坏死因子-α的产生增加会加剧炎症。它们通过 CYP2E1 的诱导以及内毒素而被激活。二亚油酰磷脂酰胆碱（多烯磷脂酰胆碱 (PPC) 的活性磷脂酰胆碱 (PC) 种类）可减少内毒素刺激的肿瘤坏死因子-α 释放。此外，过氧化物酶体增殖物激活受体α和omega脂肪酸氧化提供的防御机制很容易被压倒，特别是在雌性大鼠和肝诱导脂肪酸结合蛋白（L-FABPc）较低的女性中。因此，游离脂肪酸的细胞内浓度可能变得足够高以损伤细胞膜，从而导致坏死、炎症以及进展为纤维化和肝硬化。最终，肝脏 S-腺苷甲硫氨酸和 PC 在酒精中耗尽，其多种细胞功能受损，但可以通过补充 PC 来恢复。因此，预防和治疗脂肪变性及其进展为更严重的损伤可以通过多因素方法来实现：控制饮酒、避免肥胖和过量膳食长链脂肪酸，或用中链脂肪酸替代，以及使用 PPC 补充 S-腺苷甲硫氨酸和 PC。对酒精性脂肪肝发病机制及其向炎症和纤维化进展的了解的进展为更好地预防和治疗带来了前景。 (C) 2005 Elsevier Inc. 保留所有权利。
Liver disease in the alcoholic is due not only to malnutrition but also to ethanol's hepatotoxicity linked to its metabolism by means of the alcohol dehydrogenase and cytochrome P450 2E1 (CYP2E1) pathways and the resulting production of toxic acetaldehyde. In addition, alcohol dehydrogenase-mediated ethanol metabolism generates the reduced form of nicotinamide adenine dinuclectide (NADH), which promotes steatosis by stimulating the synthesis of fatty acids and opposing their oxidation. Steatosis is also promoted by excess dietary lipids and can be attenuated by their replacement with medium-chain triglycerides. Through reduction of pyruvate, elevated NADH also increases lactate, which stimulates collagen synthesis in myofibroblasts. Furthermore, CYP2E1 activity is inducible by its substrates, not only ethanol but also fatty acids. Their excess and metabolism by means of this pathway generate release of free radicals, which cause oxidative stress, with peroxidation of lipids and membrane damage, including altered enzyme activities. Products of lipid peroxidation such as 4-hydroxynonenal stimulate collagen generation and fibrosis, which are further increased through diminished feedback inhibition of collagen synthesis because acetaldehyde forms adducts with the carboxyl-tertninal propeptide of procollagen in hepatic stellate cells. Acetaldehyde is also toxic to the mitochondria, and it aggravates their oxidative stress by binding to reduced glutathione and promoting its leak-age. Oxidative stress and associated cellular injury promote inflammation, which is aggravated by increased production of the proinflammatory cytokine tumor necrosis factor-alpha in the Kupffer cells. These are activated by induction of their CYP2E1 as well as by endotoxin. The endotoxin-stimulated tumor necrosis factor-alpha release is decreased by dilinoleoylphosphatidylcholine, the active phosphatidylcholine (PC) species of polyenylphosphatidlcholine (PPC). Moreover, defense mechanisms provided by peroxisome proliferator-activated receptor alpha and omega fatty acid oxidation are readily overwhelmed, particularly in female rats and also in women who have low hepatic induction of fatty acid-binding protein (L-FABPc). Accordingly, the intracellular concentration of free fatty acids may become high enough to injure membranes, thereby contributing to necrosis, inflammation, and progression to fibrosis and cirrhosis. Eventually, hepatic S-adenosylmethionine and PCs become depleted in the alcoholic, with impairment of their multiple cellular functions, which can be restored by PC replenishment. Thus, prevention and therapy opposing the development of steatosis and its progression to more severe injury can be achieved by a multifactorial approach: control of alcohol consumption, avoidance of obesity and of excess dietary long-chain fatty acids, or their replacement with medium-chain fatty acids, and replenishment of S-adenosylmethionine and PCs by using PPC. Progress in the understanding of the pathogenesis of alcoholic fatty liver and its progression to inflammation and fibrosis has resulted in prospects for their better prevention and treatment. (C) 2005 Elsevier Inc. All rights reserved.