Mello Tommaso, Ceni Elisabetta, Surrenti Calogero, Galli Andrea
Gastroenterology Unit, Department of Clinical Pathophysiology, University of Florence, Florence, Italy.
Mol Aspects Med. 2008 Feb-Apr;29(1-2):17-21. doi: 10.1016/j.mam.2007.10.001. Epub 2007 Nov 21.
Alcohol abuse is one of the major causes of liver fibrosis worldwide. Although the pathogenesis of liver fibrosis is a very complex phenomenon involving different molecular and biological mechanisms, several lines of evidence established that the first ethanol metabolite, acetaldehyde, plays a key role in the onset and maintenance of the fibrogenetic process. This review briefly summarizes the molecular mechanisms underlying acetaldehyde pro-fibrogenic effects. Liver fibrosis represents a general wound-healing response to a variety of insults. Although mortality due to alcohol abuse has been constantly decreasing in the past 20 years in Southern Europe and North America, in several Eastern-European countries and Great Britain Alcoholic Liver Disease (ALD) shows a sharply increasing trend [Bosetti, C., Levi, F., Lucchini, F., Zatonski, W.A., Negri, E., La, V.C., 2007. Worldwide mortality from cirrhosis: an update to 2002. J. Hepatol. 46, 827-839]. ALD has a complex pathogenesis, in which acetaldehyde (AcCHO), the major ethanol metabolite, plays a central role. Ethanol is mainly metabolized in the liver by two oxidative pathways. In the first one ethanol is oxidized to acetaldehyde by the cytoplasmic alcohol dehydrogenase enzyme (ADH), acetaldehyde is then oxidized to acetic acid by the mitochondrial acetaldehyde dehydrogenase (ALDH). The second pathway is inducible and involves the microsomal ethanol-oxidizing system (MEOS), in which the oxidation of ethanol to acetaldehyde and acetic acid also leads to generation of reactive oxygen species (ROS). Chronic ethanol consumption significantly inhibits mitochondrial ALDH activity while the rate of ethanol oxidation to acetaldehyde is even enhanced, resulting in a striking increase of tissue and plasma acetaldehyde levels [Lieber, C.S., 1997. Ethanol metabolism, cirrhosis and alcoholism. Clin. Chim. Acta 257, 59-84]. This review will focus on the molecular mechanisms by which acetaldehyde promote liver fibrosis.
酒精滥用是全球肝纤维化的主要原因之一。尽管肝纤维化的发病机制是一个涉及不同分子和生物学机制的非常复杂的现象，但有几条证据表明，乙醇的第一种代谢产物乙醛在纤维化过程的发生和维持中起关键作用。本综述简要总结了乙醛促纤维化作用的分子机制。肝纤维化是对各种损伤的一种普遍的伤口愈合反应。尽管在过去20年里，南欧和北美的酒精滥用死亡率一直在持续下降，但在几个东欧国家和英国，酒精性肝病（ALD）呈急剧上升趋势[博塞蒂，C.，列维，F.，卢基尼，F.，扎通斯基，W.A.，内格里，E.，拉，V.C.，2007年。全球肝硬化死亡率：2002年最新情况。《肝脏病学杂志》46，827 - 839]。ALD有复杂的发病机制，其中主要的乙醇代谢产物乙醛起核心作用。乙醇主要通过两种氧化途径在肝脏中代谢。在第一种途径中，乙醇被细胞质中的酒精脱氢酶（ADH）氧化为乙醛，然后乙醛被线粒体乙醛脱氢酶（ALDH）氧化为乙酸。第二种途径是可诱导的，涉及微粒体乙醇氧化系统（MEOS），其中乙醇氧化为乙醛和乙酸的过程也会导致活性氧（ROS）的产生。长期饮酒会显著抑制线粒体ALDH的活性，而乙醇氧化为乙醛的速率甚至会加快，导致组织和血浆中乙醛水平显著升高[利伯，C.S.，1997年。乙醇代谢、肝硬化与酒精中毒。《临床化学学报》257，59 - 84]。本综述将聚焦于乙醛促进肝纤维化的分子机制。
