Ansari Rais A, Husain Kazim, Rizvi Syed A A
Department of Pharmaceutical Sciences, College of Pharmacy, Health Professions Division, Nova Southeastern University, 3200 S University Drive, Fort Lauderdale, FL 33328, USA.
Department of Physiology, Pharmacology and Toxicology, Ponce School of Medicine, P.O. Box 7004, Ponce, PR 00732-2575, USA.
Biomolecules. 2016 Jun 24;6(3):29. doi: 10.3390/biom6030029.
Chronic alcohol consumption induces multi-organ damage, including alcoholic liver disease (ALD), pancreatitis and hypertension. Ethanol and ethanol metabolic products play a significant role in the manifestation of its toxicity. Ethanol metabolizes to acetaldehyde and produces reduced nicotinamide adenine dinucleotide (NADH) by cytosolic alcohol dehydrogenase. Ethanol metabolism mediated by cytochrome-P450 2E1 causes oxidative stress due to increased production of reactive oxygen species (ROS). Acetaldehyde, increased redox cellular state and ROS activate transcription factors, which in turn activate genes for lipid biosynthesis and offer protection of hepatocytes from alcohol toxicity. Sterol regulatory element binding proteins (SREBPs) and peroxisome proliferator activated-receptors (PPARs) are two key lipogenic transcription factors implicated in the development of fatty liver in alcoholic and non-alcoholic steatohepatitis. SREBP-1 is activated in the livers of chronic ethanol abusers. An increase in ROS activates nuclear factor erythroid-2-related factor-2 (Nrf2) and hypoxia inducible factor (HIF) to provide protection to hepatocytes from ethanol toxicity. Under ethanol exposure, due to increased gut permeability, there is release of gram-negative bacteria-derived lipopolysaccharide (LPS) from intestine causing activation of immune response. In addition, the metabolic product, acetaldehyde, modifies the proteins in hepatocyte, which become antigens inviting auto-immune response. LPS activates macrophages, especially the liver resident macrophages, Kupffer cells. These Kupffer cells and circulating macrophages secrete various cytokines. The level of tumor necrosis factor-α (TNFα), interleukin-1beta (IL-1β), IL-6, IL-8 and IL-12 have been found elevated among chronic alcoholics. In addition to elevation of these cytokines, the peripheral iron (Fe(2+)) is also mobilized. An increased level of hepatic iron has been observed among alcoholics. Increased ROS, IL-1β, acetaldehyde, and increased hepatic iron, all activate nuclear factor-kappa B (NF-κB) transcription factor. Resolution of increased reactive oxygen species requires increased expression of genes responsible for dismutation of increased ROS which is partially achieved by IL-6 mediated activation of signal transducers and activators of transcription 3 (STAT3). In addition to these transcription factors, activator protein-1 may also be activated in hepatocytes due to its association with resolution of increased ROS. These transcription factors are central to alcohol-mediated hepatotoxicity.
长期饮酒会导致多器官损伤，包括酒精性肝病（ALD）、胰腺炎和高血压。乙醇及其代谢产物在其毒性表现中起重要作用。乙醇代谢为乙醛，并通过胞质醇脱氢酶产生还原型烟酰胺腺嘌呤二核苷酸（NADH）。细胞色素P450 2E1介导的乙醇代谢由于活性氧（ROS）生成增加而导致氧化应激。乙醛、细胞氧化还原状态的改变和ROS激活转录因子，进而激活脂质生物合成相关基因，并保护肝细胞免受酒精毒性。固醇调节元件结合蛋白（SREBPs）和过氧化物酶体增殖物激活受体（PPARs）是与酒精性和非酒精性脂肪性肝炎中脂肪肝发生相关的两个关键脂肪生成转录因子。SREBP-1在慢性乙醇滥用者的肝脏中被激活。ROS的增加激活核因子红细胞2相关因子2（Nrf2）和缺氧诱导因子（HIF），以保护肝细胞免受乙醇毒性。在乙醇暴露下，由于肠道通透性增加，肠道中革兰氏阴性菌衍生的脂多糖（LPS）释放，导致免疫反应激活。此外，代谢产物乙醛会修饰肝细胞中的蛋白质，使其成为引发自身免疫反应的抗原。LPS激活巨噬细胞，尤其是肝脏驻留巨噬细胞库普弗细胞。这些库普弗细胞和循环巨噬细胞分泌各种细胞因子。在慢性酗酒者中发现肿瘤坏死因子-α（TNFα）、白细胞介素-1β（IL-1β）、IL-6、IL-8和IL-12水平升高。除了这些细胞因子升高外，外周铁（Fe(2+)）也会被动员。在酗酒者中观察到肝脏铁水平升高。ROS增加、IL-1β、乙醛和肝脏铁增加均激活核因子-κB（NF-κB）转录因子。活性氧增加的消除需要负责增加的ROS歧化的基因表达增加，这部分是通过IL-6介导的信号转导和转录激活因子3（STAT3）的激活来实现的。除了这些转录因子外，激活蛋白-1也可能在肝细胞中被激活，因为它与增加的ROS的消除有关。这些转录因子在酒精介导的肝毒性中起核心作用。
