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Biomolecules 2016, 6(3), 29; doi:10.3390/biom6030029

Role of Transcription Factors in Steatohepatitis and Hypertension after Ethanol: The Epicenter of Metabolism

1
Department of Pharmaceutical Sciences, College of Pharmacy, Health Professions Division, Nova Southeastern University, 3200 S University Drive, Fort Lauderdale, FL 33328, USA
2
Department of Physiology, Pharmacology and Toxicology, Ponce School of Medicine, P.O. Box 7004, Ponce, PR 00732-2575, USA
*
Author to whom correspondence should be addressed.
Academic Editors: Natalia Osna and Kusum Kharbanda
Received: 31 August 2015 / Revised: 25 May 2016 / Accepted: 8 June 2016 / Published: 24 June 2016
(This article belongs to the Collection Multi-Organ Alcohol-Related Damage: Mechanisms and Treatment)
View Full-Text   |   Download PDF [564 KB, uploaded 24 June 2016]   |  

Abstract

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. View Full-Text
Keywords: ethanol; alcoholic liver disease; steatohepatitis; hypertension; transcription factor; gene regulation ethanol; alcoholic liver disease; steatohepatitis; hypertension; transcription factor; gene regulation
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MDPI and ACS Style

Ansari, R.A.; Husain, K.; Rizvi, S.A.A. Role of Transcription Factors in Steatohepatitis and Hypertension after Ethanol: The Epicenter of Metabolism. Biomolecules 2016, 6, 29.

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