Role of Transcription Factors in Steatohepatitis and Hypertension after Ethanol: The Epicenter of Metabolism.
Role of Transcription Factors in Steatohepatitis and Hypertension after Ethanol: The Epicenter of Metabolism.
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DOI：
10.3390/biom6030029
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发表时间：
2016-06-24
期刊：
影响因子：
5.5
通讯作者：
Rizvi SA
中科院分区：
文献类型：
--
作者：
Ansari RA;Husain K;Rizvi SA
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。乙醇和乙醇代谢产物对其毒性的表现起着重要作用。乙醇代谢为乙醛，并通过胞质乙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 介导的乙醇代谢会因活性氧 (ROS) 产生增加而引起氧化应激。乙醛、增加的氧化还原细胞状态和活性氧激活转录因子，进而激活脂质生物合成基因并保护肝细胞免受酒精毒性。甾醇调节元件结合蛋白（SREBP）和过氧化物酶体增殖物激活受体（PPAR）是两个关键的脂肪生成转录因子，与酒精性和非酒精性脂肪性肝炎中脂肪肝的发展有关。 SREBP-1 在慢性酒精滥用者的肝脏中被激活。 ROS 的增加会激活核因子红细胞 2 相关因子 2 (Nrf2) 和缺氧诱导因子 (HIF)，从而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，革兰氏阴性菌衍生的脂多糖（LPS）从肠道释放，引起免疫反应激活。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，尤其是肝脏驻留的巨噬细胞，库普弗细胞。这些枯否细胞和循环巨噬细胞分泌各种细胞因子。研究发现，慢性酗酒者的肿瘤坏死因子-α (TNFα)、白细胞介素-1β (IL-1β)、IL-6、IL-8 和 IL-12 水平升高。除了这些细胞因子的升高外，外周铁 (Fe2+) 也被动员起来。在酗酒者中观察到肝铁水平升高。 ROS、IL-1β、乙醛的增加和肝铁的增加，都会激活核因子-κB (NF-κB) 转录因子。解决增加的活性氧需要增加负责 ROS 歧化的基因的表达，这部分是通过 IL-6 介导的信号转导器和转录激活剂 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 的分解有关。这些转录因子是酒精介导的肝毒性的核心。
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 (Fe2+) 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.
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DOI：
10.1124/jpet.102.047217
发表时间：
2003-09-01
影响因子：
3.5
作者：
Enomoto, N;Takei, Y;Sato, N
通讯作者：
Sato, N
DOI：
10.1152/ajpgi.1996.271.3.g494
发表时间：
1996-09-01
影响因子：
4.5
作者：
Arteel, GE;Raleigh, JA;Thurman, RG
通讯作者：
Thurman, RG
DOI：
10.1016/s1096-4959(02)00006-4
发表时间：
2002-03-01
影响因子：
2.2
作者：
Carrasco, MP;Jiménez-López, JM;Marco, C
通讯作者：
Marco, C
影响因子：
37.8
作者：
Cheng, Che-Ping;Cheng, Heng-Jie;Little, William C.
通讯作者：
Little, William C.
影响因子：
10.8
作者：
GOULD, AB;GREEN, D
通讯作者：
GREEN, D