{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T09:52:09Z","timestamp":1791193929600,"version":"4.1.0"},"reference-count":135,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2016,6,24]],"date-time":"2016-06-24T00:00:00Z","timestamp":1466726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>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-\u03b1 (TNF\u03b1), interleukin-1beta (IL-1\u03b2), 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-1\u03b2, acetaldehyde, and increased hepatic iron, all activate nuclear factor-kappa B (NF-\u03baB) 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.<\/jats:p>","DOI":"10.3390\/biom6030029","type":"journal-article","created":{"date-parts":[[2016,6,25]],"date-time":"2016-06-25T21:21:45Z","timestamp":1466889705000},"page":"29","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":48,"title":["Role of Transcription Factors in Steatohepatitis and Hypertension after Ethanol: The Epicenter of Metabolism"],"prefix":"10.3390","volume":"6","author":[{"given":"Rais","family":"Ansari","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Health Professions Division, Nova Southeastern University, 3200 S University Drive, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazim","family":"Husain","sequence":"additional","affiliation":[{"name":"Department of Physiology, Pharmacology and Toxicology, Ponce School of Medicine, P.O. Box 7004, Ponce, PR 00732-2575, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0162-5294","authenticated-orcid":false,"given":"Syed","family":"Rizvi","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy, Health Professions Division, Nova Southeastern University, 3200 S University Drive, Fort Lauderdale, FL 33328, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2016,6,24]]},"reference":[{"key":"ref_1","unstructured":"McGovern, P.E. (2003). Ancient Wine: The Search for Origins of Viniculture, Princeton University Press."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1146\/annurev.anthro.35.081705.123120","article-title":"Alcohol: Anthropological\/archaeological perspectives","volume":"35","author":"Dietler","year":"2006","journal-title":"Annu. Rev. Anthropol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.yjmcc.2011.10.011","article-title":"Moderate ethanol ingestion and cardiovascular protection: From epidemiologic associations to cellular mechanisms","volume":"52","author":"Krenz","year":"2012","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"39","DOI":"10.2174\/1874473711003010039","article-title":"Cardioprotection by regular ethanol consumption: Potential mechanisms and clinical application","volume":"3","author":"Miyamae","year":"2010","journal-title":"Curr. Drug Abuse Rev."},{"key":"ref_5","unstructured":"Hanson, D.J. (1995). Preventing Alcohol Abuse: Alcohol, Culture and Control, Greenwood Publishing Group."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.phrs.2004.10.005","article-title":"Dose response of alcohol-induced changes in BP, nitric oxide and antioxidants in rat plasma","volume":"51","author":"Husain","year":"2005","journal-title":"Pharmacol. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1016\/j.biopsych.2004.03.006","article-title":"Alcohol use disorders and mood disorders: A national institute on alcohol abuse and alcoholism perspective","volume":"56","author":"Li","year":"2004","journal-title":"Biol. Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2207","DOI":"10.1001\/jama.1993.03510180077038","article-title":"Actual causes of death in the United States","volume":"270","author":"McGinnis","year":"1993","journal-title":"JAMA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9","DOI":"10.15288\/jsa.1998.59.9","article-title":"Hepatic and other medical disorders of alcoholism: From pathogenesis to treatment","volume":"59","author":"Lieber","year":"1998","journal-title":"J. Stud. Alcohol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"245","DOI":"10.4330\/wjc.v6.i5.245","article-title":"Alcohol-induced hypertension: Mechanism and prevention","volume":"6","author":"Husain","year":"2014","journal-title":"World J. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1016\/S0002-9440(10)63473-6","article-title":"A critical involvement of oxidative stress in acute alcohol-induced hepatic TNF-alpha production","volume":"163","author":"Zhou","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1111\/j.1530-0277.1984.tb05689.x","article-title":"Ethanol and lipids","volume":"8","author":"Lieber","year":"1984","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/S1096-4959(02)00006-4","article-title":"Comparative study of the effects of short- and long-term ethanol treatment and alcohol withdrawal on phospholipid biosynthesis in rat hepatocytes","volume":"131","author":"Carrasco","year":"2002","journal-title":"Comp. Biochem. Physiol. B Biochem. Mol. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1016\/S0024-3205(00)01035-3","article-title":"Chronic ingestion of ethanol stimulates lipogenic response in rat hepatocytes","volume":"68","author":"Carrasco","year":"2001","journal-title":"Life Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1111\/j.1742-4658.2008.06806.x","article-title":"SREBPs: Physiology and pathophysiology of the SREBP family","volume":"276","author":"Shimano","year":"2009","journal-title":"FEBS J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.biochi.2004.09.018","article-title":"SREBP transcription factors: Master regulators of lipid homeostasis","volume":"86","author":"Eberle","year":"2004","journal-title":"Biochimie"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/S0163-7827(01)00010-8","article-title":"Sterol regulatory element-binding proteins (SREBPs): Transcriptional regulators of lipid synthetic genes","volume":"40","author":"Shimano","year":"2001","journal-title":"Prog. Lipid Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1053\/gast.2003.50089","article-title":"Acetaldehyde impairs mitochondrial glutathione transport in HepG2 cells through endoplasmic reticulum stress","volume":"124","author":"Lluis","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"29342","DOI":"10.1074\/jbc.M202411200","article-title":"Ethanol induces fatty acid synthesis pathways by activation of sterol regulatory element-binding protein (SREBP)","volume":"277","author":"You","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.alcohol.2004.07.004","article-title":"Molecular mechanisms of alcoholic fatty liver: Role of sterol regulatory element-binding proteins","volume":"34","author":"You","year":"2004","journal-title":"Alcohol"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1016\/S0016-5085(03)00276-2","article-title":"Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice","volume":"124","author":"Ji","year":"2003","journal-title":"Gastroenterology"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Grygiel-Gorniak, B. (2014). Peroxisome proliferator-activated receptors and their ligands: Nutritional and clinical implications\u2014A review. Nutr. J.","DOI":"10.1186\/1475-2891-13-17"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1074\/jbc.M008791200","article-title":"The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor alpha is inhibited by ethanol metabolism. A novel mechanism for the development of ethanol-induced fatty liver","volume":"276","author":"Galli","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"27997","DOI":"10.1074\/jbc.M302140200","article-title":"Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice","volume":"278","author":"Fischer","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"G1","DOI":"10.1152\/ajpgi.00056.2004","article-title":"Recent advances in alcoholic liver disease II. Minireview: Molecular mechanisms of alcoholic fatty liver","volume":"287","author":"You","year":"2004","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2416","DOI":"10.1172\/JCI119424","article-title":"Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids","volume":"99","author":"Considine","year":"1997","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5495","DOI":"10.1128\/MCB.19.8.5495","article-title":"Regulation of peroxisome proliferator-activated receptor gamma expression by adipocyte differentiation and determination factor 1\/sterol regulatory element binding protein 1: Implications for adipocyte differentiation and metabolism","volume":"19","author":"Fajas","year":"1999","journal-title":"Mol. Cell. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4333","DOI":"10.1073\/pnas.95.8.4333","article-title":"ADD1\/SREBP1 activates PPARgamma through the production of endogenous ligand","volume":"95","author":"Kim","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1172\/JCI200317223","article-title":"Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes","volume":"111","author":"Matsusue","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1074\/jbc.M210062200","article-title":"Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor gamma1 (PPARgamma1) overexpression","volume":"278","author":"Yu","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"E1195","DOI":"10.1152\/ajpendo.00513.2004","article-title":"PPARgamma2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes","volume":"288","author":"Schadinger","year":"2005","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"34268","DOI":"10.1074\/jbc.M300043200","article-title":"Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass","volume":"278","author":"Gavrilova","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1101\/gad.10.9.1096","article-title":"ADD1\/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism","volume":"10","author":"Kim","year":"1996","journal-title":"Genes Dev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1101\/gad.948702","article-title":"C\/EBPalpha induces adipogenesis through PPARgamma: A unified pathway","volume":"16","author":"Rosen","year":"2002","journal-title":"Genes Dev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"S104","DOI":"10.1111\/j.1440-1746.2007.05294.x","article-title":"Fat paradox of steatohepatitis","volume":"23","author":"Tsukamoto","year":"2008","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.mrfmmm.2009.09.009","article-title":"Role of PPAR-gamma in inflammation. Prospects for therapeutic intervention by food components","volume":"690","author":"Martin","year":"2010","journal-title":"Mutat. Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1016\/S0006-291X(03)00407-8","article-title":"Ethanol feeding induces insulin resistance with enhanced PI 3-kinase activation","volume":"303","author":"Onishi","year":"2003","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1124\/jpet.102.047217","article-title":"Prevention of ethanol-induced liver injury in rats by an agonist of peroxisome proliferator-activated receptor-gamma, pioglitazone","volume":"306","author":"Enomoto","year":"2003","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1002\/hep.1840090302","article-title":"Increased tumor necrosis factor production by monocytes in alcoholic hepatitis","volume":"9","author":"McClain","year":"1989","journal-title":"Hepatology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1016\/j.jhep.2009.03.007","article-title":"Signalling pathways in alcohol-induced liver inflammation","volume":"50","author":"Mandrekar","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1002\/hep.1840130211","article-title":"Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients","volume":"13","author":"Khoruts","year":"1991","journal-title":"Hepatology"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1053\/j.gastro.2007.09.034","article-title":"Abrogation of the antifibrotic effects of natural killer cells\/interferon-gamma contributes to alcohol acceleration of liver fibrosis","volume":"134","author":"Jeong","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1172\/JCI13505","article-title":"Role of AMP-activated protein kinase in mechanism of metformin action","volume":"108","author":"Zhou","year":"2001","journal-title":"J. Clin. Investig."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1172\/JCI200317797","article-title":"The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice","volume":"112","author":"Xu","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1843","DOI":"10.1016\/j.biocel.2007.05.002","article-title":"Endoplasmic reticulum stress causes the activation of sterol regulatory element binding protein-2","volume":"39","author":"Colgan","year":"2007","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Ji, C. (2012). Mechanisms of alcohol-induced endoplasmic reticulum stress and organ injuries. Biochem. Res. Int.","DOI":"10.1155\/2012\/216450"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1111\/j.1530-0277.2011.01602.x","article-title":"Alcohol disrupts endoplasmic reticulum function and protein secretion in hepatocytes","volume":"36","author":"Howarth","year":"2012","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1146\/annurev.nutr.24.012003.132258","article-title":"Molecular aspects of alcohol metabolism: Transcription factors involved in early ethanol-induced liver injury","volume":"24","author":"Nagy","year":"2004","journal-title":"Annu. Rev. Nutr."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.cmet.2011.03.009","article-title":"AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice","volume":"13","author":"Li","year":"2011","journal-title":"Cell Metab."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1002\/hep.24708","article-title":"Regulation of hepatic lipin-1 by ethanol: Role of AMP-activated protein kinase\/sterol regulatory element-binding protein 1 signaling in mice","volume":"55","author":"Hu","year":"2012","journal-title":"Hepatology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5053","DOI":"10.1074\/jbc.273.9.5053","article-title":"Tumor necrosis factor-alpha stimulates the maturation of sterol regulatory element binding protein-1 in human hepatocytes through the action of neutral sphingomyelinase","volume":"273","author":"Lawler","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1111\/j.1530-0277.2012.01773.x","article-title":"Carvedilol attenuates the progression of alcohol fatty liver disease in rats","volume":"36","author":"Liu","year":"2012","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"27948","DOI":"10.1074\/jbc.M313920200","article-title":"Human CCAAT\/enhancer-binding protein beta gene expression is activated by endoplasmic reticulum stress through an unfolded protein response element downstream of the protein coding sequence","volume":"279","author":"Chen","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"29279","DOI":"10.1074\/jbc.273.45.29279","article-title":"The role of C\/EBP isoforms in the control of inflammatory and native immunity functions","volume":"273","author":"Poli","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"43572","DOI":"10.1074\/jbc.M204535200","article-title":"Ethanol induction of class I alcohol dehydrogenase expression in the rat occurs through alterations in CCAAT\/enhancer binding proteins beta and gamma","volume":"277","author":"He","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1053\/j.gastro.2004.01.020","article-title":"The effect of alcohol consumption on the prevalence of iron overload, iron deficiency, and iron deficiency anemia","volume":"126","author":"Ioannou","year":"2004","journal-title":"Gastroenterology"},{"key":"ref_57","first-page":"G1240","article-title":"Iron primes hepatic macrophages for NF-kappaB activation in alcoholic liver injury","volume":"277","author":"Tsukamoto","year":"1999","journal-title":"Am. J. Physiol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/S0741-8329(03)00100-9","article-title":"Iron-dependent activation of NF-kappaB in Kupffer cells: A priming mechanism for alcoholic liver disease","volume":"30","author":"Xiong","year":"2003","journal-title":"Alcohol"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"G719","DOI":"10.1152\/ajpgi.00108.2002","article-title":"Iron activates NF-kappaB in Kupffer cells","volume":"283","author":"She","year":"2002","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1111\/j.1530-0277.1985.tb05525.x","article-title":"Ethanol oxidation by hydroxyl radicals: Role of iron chelates, superoxide, and hydrogen peroxide","volume":"9","author":"Feierman","year":"1985","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1391","DOI":"10.1111\/j.1530-0277.2009.00969.x","article-title":"Hepcidin regulation in wild-type and Hfe knockout mice in response to alcohol consumption: Evidence for an alcohol-induced hypoxic response","volume":"33","author":"Heritage","year":"2009","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_62","first-page":"245","article-title":"Overview: How is alcohol metabolized by the body?","volume":"29","author":"Zakhari","year":"2006","journal-title":"Alcohol Res. Health"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Aaltonen, T., Abazov, V.M., Abbott, B., Acharya, B.S., Adams, M., Adams, T., Agnew, J.P., Alexeev, G.D., Alkhazov, G., and Alton, A. (2014). Observation of s-channel production of single top quarks at the tevatron. Phys. Rev. Lett.","DOI":"10.1103\/PhysRevLett.112.231803"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1002\/hep.510250422","article-title":"Chronic enteral ethanol treatment causes hypoxia in rat liver tissue in vivo","volume":"25","author":"Arteel","year":"1997","journal-title":"Hepatology"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1016\/j.bbabio.2011.09.011","article-title":"Nitric oxide and hypoxia exacerbate alcohol-induced mitochondrial dysfunction in hepatocytes","volume":"1807","author":"Zelickson","year":"2011","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_66","unstructured":"Aaltonen, T., Amerio, S., Amidei, D., Anastassov, A., Annovi, A., Antos, J., Apollinari, G., Appel, J.A., Arisawa, T., and Artikov, A. (2014). Search for s-channel single-top-quark production in events with missing energy plus jets in pp collisions at sqrt[s]=1.96 TeV. Phys. Rev. Lett."},{"key":"ref_67","first-page":"G494","article-title":"Acute alcohol produces hypoxia directly in rat liver tissue in vivo: Role of Kupffer cells","volume":"271","author":"Arteel","year":"1996","journal-title":"Am. J. Physiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1016\/0091-3057(83)90215-0","article-title":"Effect of acute and chronic ethanol consumption on hepatic tissue oxygen tension in rats","volume":"18","author":"Sato","year":"1983","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"25130","DOI":"10.1074\/jbc.M001914200","article-title":"Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: A mechanism of O2 sensing","volume":"275","author":"Chandel","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1158\/0008-5472.CAN-07-2489","article-title":"Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and sterol regulatory element binding protein-1","volume":"68","author":"Furuta","year":"2008","journal-title":"Cancer Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"561","DOI":"10.2174\/1566524033479537","article-title":"Peroxisome proliferator-activated receptors, fatty acid oxidation, steatohepatitis and hepatocarcinogenesis","volume":"3","author":"Yu","year":"2003","journal-title":"Curr. Mol. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1002\/hep.24148","article-title":"Nuclear receptors in liver disease","volume":"53","author":"Wagner","year":"2011","journal-title":"Hepatology"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1002\/hep.22222","article-title":"Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice","volume":"47","author":"Lu","year":"2008","journal-title":"Hepatology"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1042\/CS20130064","article-title":"Impact of PPAR-alpha induction on glucose homoeostasis in alcohol-fed mice","volume":"125","author":"Lebrun","year":"2013","journal-title":"Clin. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1161\/CIRCRESAHA.107.164384","article-title":"Peroxisome proliferator-activated receptor-gamma-mediated effects in the vasculature","volume":"102","author":"Duan","year":"2008","journal-title":"Circ. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0006-2952(01)00817-6","article-title":"Toxicological consequences of altered peroxisome proliferator-activated receptor gamma (PPARgamma) expression in the liver: Insights from models of obesity and type 2 diabetes","volume":"63","author":"Boelsterli","year":"2002","journal-title":"Biochem. Pharmacol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"4021","DOI":"10.1210\/endo.141.11.7771","article-title":"Up-regulation of peroxisome proliferator-activated receptors (PPAR-alpha) and PPAR-gamma messenger ribonucleic acid expression in the liver in murine obesity: Troglitazone induces expression of PPAR-gamma-responsive adipose tissue-specific genes in the liver of obese diabetic mice","volume":"141","author":"Memon","year":"2000","journal-title":"Endocrinology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1023\/A:1011927113563","article-title":"Hepatic over-expression of peroxisome proliferator activated receptor gamma2 in the ob\/ob mouse model of non-insulin dependent diabetes mellitus","volume":"224","author":"Rahimian","year":"2001","journal-title":"Mol. Cell. Biochem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/0024-3205(94)00953-8","article-title":"Expression of the peroxisome proliferator-activated receptor gene is decreased in experimental alcoholic liver disease","volume":"56","author":"Wan","year":"1995","journal-title":"Life Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"270","DOI":"10.2310\/JIM.0b013e31827c2795","article-title":"Activation of carbohydrate response element-binding protein by ethanol","volume":"61","author":"Liangpunsakul","year":"2013","journal-title":"J. Investig. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"G1004","DOI":"10.1152\/ajpgi.00482.2009","article-title":"Inhibitory effect of ethanol on AMPK phosphorylation is mediated in part through elevated ceramide levels","volume":"298","author":"Liangpunsakul","year":"2010","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"G1173","DOI":"10.1152\/ajpgi.90349.2008","article-title":"Effect of ethanol on hydrogen peroxide-induced AMPK phosphorylation","volume":"295","author":"Liangpunsakul","year":"2008","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"15597","DOI":"10.1073\/pnas.0405238101","article-title":"Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription","volume":"101","author":"Ishii","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"2176","DOI":"10.1172\/JCI41636","article-title":"The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans","volume":"122","author":"Benhamed","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"9924","DOI":"10.3390\/ijms15069924","article-title":"Steatosis and steatohepatitis: Complex disorders","volume":"15","author":"Bettermann","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"7281","DOI":"10.1073\/pnas.0401516101","article-title":"Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis","volume":"101","author":"Iizuka","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1507\/endocrj.K07E-110","article-title":"ChREBP: A glucose-activated transcription factor involved in the development of metabolic syndrome","volume":"55","author":"Iizuka","year":"2008","journal-title":"Endocr J."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/0006-8993(93)91721-4","article-title":"Induction of brain cytochrome P-450IIE1 by chronic ethanol treatment","volume":"601","author":"Anandatheerthavarada","year":"1993","journal-title":"Brain Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1007\/s00253-002-1158-6","article-title":"Overview of tag protein fusions: From molecular and biochemical fundamentals to commercial systems","volume":"60","author":"Terpe","year":"2003","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/S0891-5849(99)00138-0","article-title":"Ethanol stimulates the production of reactive oxygen species at mitochondrial complexes I and III","volume":"27","author":"Bailey","year":"1999","journal-title":"Free Radic. Biol. Med."},{"key":"ref_91","first-page":"G7","article-title":"GSH transport in mitochondria: Defense against TNF-induced oxidative stress and alcohol-induced defect","volume":"273","author":"Kaplowitz","year":"1997","journal-title":"Am. J. Physiol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"13291","DOI":"10.1074\/jbc.R900010200","article-title":"The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress","volume":"284","author":"Nguyen","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.taap.2009.06.009","article-title":"NRF2 signaling and cell survival","volume":"244","author":"Niture","year":"2010","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Vargas, M.R., and Johnson, J.A. (2009). The NRF2-ARE cytoprotective pathway in astrocytes. Expert Rev. Mol. Med.","DOI":"10.1017\/S1462399409001094"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1146\/annurev-pharmtox-011112-140320","article-title":"Role of NRF2 in oxidative stress and toxicity","volume":"53","author":"Ma","year":"2013","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Shin, S.M., Yang, J.H., and Ki, S.H. (2013). Role of the NRF2-ARE pathway in liver diseases. Oxid. Med. Cell. Longev.","DOI":"10.1155\/2013\/763257"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1053\/j.gastro.2008.01.011","article-title":"Nuclear factor-eythroid 2-related factor 2 prevents alcohol-induced fulminant liver injury","volume":"134","author":"Lamle","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Ni, H.M., Bhakta, A., Wang, S., Li, Z., Manley, S., Huang, H., Copple, B., and Ding, W.X. (2014). Role of hypoxia inducing factor-1beta in alcohol-induced autophagy, steatosis and liver injury in mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115849"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.freeradbiomed.2013.05.009","article-title":"Cytochrome P450 2E1 potentiates ethanol induction of hypoxia and HIF-1alpha in vivo","volume":"63","author":"Wang","year":"2013","journal-title":"Free Radic. Biol. Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1016\/j.semcdb.2005.03.010","article-title":"Reactive oxygen species in the control of hypoxia-inducible factor-mediated gene expression","volume":"16","author":"Kietzmann","year":"2005","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"16767","DOI":"10.1074\/jbc.M901790200","article-title":"Genome-wide association of hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha DNA binding with expression profiling of hypoxia-inducible transcripts","volume":"284","author":"Mole","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.jhep.2011.07.024","article-title":"HIF-1alpha induction suppresses excessive lipid accumulation in alcoholic fatty liver in mice","volume":"56","author":"Nishiyama","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.jhep.2011.09.009","article-title":"HIF-1alpha is a major and complex player in alcohol induced liver diseases","volume":"56","author":"Mehal","year":"2012","journal-title":"J. Hepatol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1526","DOI":"10.1002\/hep.24256","article-title":"Hepatocyte-specific hypoxia-inducible factor-1alpha is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice","volume":"53","author":"Nath","year":"2011","journal-title":"Hepatology"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"2276","DOI":"10.1038\/onc.2008.21","article-title":"The FoxO code","volume":"27","author":"Calnan","year":"2008","journal-title":"Oncogene"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.redox.2015.06.019","article-title":"Redox regulation of FoxO transcription factors","volume":"6","author":"Klotz","year":"2015","journal-title":"Redox Biol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"30107","DOI":"10.1074\/jbc.M705325200","article-title":"The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor","volume":"282","author":"Greer","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1016\/j.ajpath.2013.08.011","article-title":"Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity","volume":"183","author":"Ni","year":"2013","journal-title":"Am. J. Pathol."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1002\/hep.26618","article-title":"Regulation of FOXO3 by phosphorylation and methylation in hepatitis C virus infection and alcohol exposure","volume":"59","author":"Tikhanovich","year":"2014","journal-title":"Hepatology"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1002\/hep.510280321","article-title":"Chronic alcohol intake reduces retinoic acid concentration and enhances AP-1 (c-Jun and c-Fos) expression in rat liver","volume":"28","author":"Wang","year":"1998","journal-title":"Hepatology"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"5964","DOI":"10.4049\/jimmunol.0901564","article-title":"Ethanol augments RANTES\/CCL5 expression in rat liver sinusoidal endothelial cells and human endothelial cells via activation of NF-kappa B, HIF-1 alpha, and AP-1","volume":"183","author":"Yeligar","year":"2009","journal-title":"J. Immunol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.1016\/S0140-6736(95)90110-8","article-title":"Alcohol and hypertension","volume":"345","author":"Kaplan","year":"1995","journal-title":"Lancet"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1161\/01.HYP.0000218586.21932.3c","article-title":"Alcohol and hypertension: An update","volume":"47","author":"Beilin","year":"2006","journal-title":"Hypertension"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1161\/01.HYP.0000146538.26193.60","article-title":"Alcohol-associated hypertension: When one drinks makes a difference","volume":"44","author":"Klatsky","year":"2004","journal-title":"Hypertension"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1161\/01.HYP.9.2.111","article-title":"Alcohol consumption and hypertension","volume":"9","author":"MacMahon","year":"1987","journal-title":"Hypertension"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1001\/archfami.3.2.150","article-title":"Alcohol and hypertension","volume":"3","author":"Grogan","year":"1994","journal-title":"Arch. Fam. Med."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1056\/NEJM199506293322601","article-title":"Suppression of alcohol-induced hypertension by dexamethasone","volume":"332","author":"Randin","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"930","DOI":"10.1038\/ajh.2008.189","article-title":"Increased circulating vasopressin may account for ethanol-induced hypertension in rats","volume":"21","author":"Resstel","year":"2008","journal-title":"Am. J. Hypertens."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1291\/hypres.31.345","article-title":"Effects of antihypertensive drugs on alcohol-induced functional responses of cultured human endothelial cells","volume":"31","author":"Soardo","year":"2008","journal-title":"Hypertens. Res."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1093\/cvr\/5.1.86","article-title":"Kinetics of the human renin and human substrate reaction","volume":"5","author":"Gould","year":"1971","journal-title":"Cardiovasc. Res."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1709","DOI":"10.1152\/jappl.1966.21.6.1709","article-title":"Renin activity during supine exercise in normotensives and hypertensives","volume":"21","author":"Fasola","year":"1966","journal-title":"J. Appl. Physiol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1097\/00004872-199205000-00011","article-title":"Abnormalities of glucocorticoid metabolism and the renin-angiotensin system: A four-corners approach to the identification of genetic determinants of blood pressure","volume":"10","author":"Watt","year":"1992","journal-title":"J. Hypertens."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1172\/JCI112566","article-title":"Angiotensinogen gene is expressed and differentially regulated in multiple tissues of the rat","volume":"78","author":"Campbell","year":"1986","journal-title":"J. Clin. Investig."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"31334","DOI":"10.1016\/S0021-9258(18)31697-1","article-title":"Angiotensinogen-deficient mice with hypotension","volume":"269","author":"Tanimoto","year":"1994","journal-title":"J. Biol. Chem."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"2735","DOI":"10.1073\/pnas.92.7.2735","article-title":"Genetic control of blood pressure and the angiotensinogen locus","volume":"92","author":"Kim","year":"1995","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_126","first-page":"H2392","article-title":"Intravenous angiotensinogen antisense in AAV-based vector decreases hypertension","volume":"277","author":"Tang","year":"1999","journal-title":"Am. J. Physiol."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1161\/01.HYP.29.1.150","article-title":"Angiotensin-converting enzyme gene mutations, blood pressures, and cardiovascular homeostasis","volume":"29","author":"Krege","year":"1997","journal-title":"Hypertension"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"250","DOI":"10.4254\/wjh.v3.i9.250","article-title":"Binge ethanol intake in chronically exposed rat liver decreases LDL-receptor and increases angiotensinogen gene expression","volume":"3","author":"Aroor","year":"2011","journal-title":"World J. Hepatol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1111\/j.1440-1681.2008.05107.x","article-title":"Activation of reactive oxygen species and the renin-angiotensin system in IgA nephropathy model mice","volume":"36","author":"Ohashi","year":"2009","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s11010-007-9583-6","article-title":"Chronic alcohol-induced oxidative endothelial injury relates to angiotensin II levels in the rat","volume":"307","author":"Husain","year":"2008","journal-title":"Mol. Cell. Biochem."},{"key":"ref_131","first-page":"34","article-title":"Fetal alcohol syndrome","volume":"82","author":"Wright","year":"1986","journal-title":"Nurs. Times"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/0741-8329(86)90053-4","article-title":"Mild but prolonged elevation of serum angiotensin converting enzyme (ACE) activity in alcoholics","volume":"3","author":"Okuno","year":"1986","journal-title":"Alcohol"},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1161\/CIRCULATIONAHA.105.596494","article-title":"Angiotensin II type 1 receptor blockade prevents alcoholic cardiomyopathy","volume":"114","author":"Cheng","year":"2006","journal-title":"Circulation"},{"key":"ref_134","unstructured":"Ansari, R.A., and Clark, M.A. (2011, January 6\u201310). Regulation of angiotensinogen gene after ethanol in hepatocytes. Proceedings of the 50th Anniversary and Annual Meeting, Society of Toxicology, Washington, DC, USA."},{"key":"ref_135","unstructured":"Ansari, R.A., Rizvi, S.A.A., and Clark, M.A. (2012, January 12\u201314). Angiotensinogen gene regulation after ethanol exposure in hepatocytes. Proceedings of the World Congress on Gastroenterology and Urology, Omaha, NE, USA."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/6\/3\/29\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:24:43Z","timestamp":1760210683000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/6\/3\/29"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6,24]]},"references-count":135,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2016,9]]}},"alternative-id":["biom6030029"],"URL":"https:\/\/doi.org\/10.3390\/biom6030029","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,6,24]]}}}