Mitochondrial dysfunction and tissue injury by alcohol, high fat, nonalcoholic substances and pathological conditions through post-translational protein modifications

Redox Biology - Tập 3 - Trang 109-123 - 2014
Byoung-Joon Song1, Mohammed Akbar1, Mohamed A. Abdelmegeed1, Kyunghee Byun2, Bonghee Lee2, Seung Kew Yoon3, James P. Hardwick4
1Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, MD 20892, USA
2Center for Genomics and Proteomics, Lee Gil Ya Cancer and Diabetes Institute, Gachon University Medical School, Incheon, Republic of Korea
3Catholic University College of Medicine Liver Research Center, Seoul, Republic of Korea
4Biochemistry and Molecular Pathology in Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA

Tài liệu tham khảo

Soboll, 1995, Regulation of energy metabolism in liver, Journal of Bioenergetics and Biomembranes, 27, 571, 10.1007/BF02111655 Dimmer, 2006, (De)constructing mitochondria: What for?, Physiology (Bethesda, Md.), 21, 233 Galloway, 2013, Mitochondrial morphology in metabolic diseases, Antioxidants and Redox Signaling, 19, 415, 10.1089/ars.2012.4779 Hoek, 2002, Alcohol and mitochondria: a dysfunctional relationship, Gastroenterology, 122, 2049, 10.1053/gast.2002.33613 Mantena, 2008, Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases, Free Radical Biology & Medicine, 44, 1259, 10.1016/j.freeradbiomed.2007.12.029 Wu, 2009, Oxidative stress and alcoholic liver disease, Seminars in Liver Disease, 29, 141, 10.1055/s-0029-1214370 Sanyal, 2001, Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities, Gastroenterology, 120, 1183, 10.1053/gast.2001.23256 Gambino, 2011, Redox balance in the pathogenesis of nonalcoholic fatty liver disease: Mechanisms and therapeutic opportunities, Antioxidants and Redox Signaling, 15, 1325, 10.1089/ars.2009.3058 Blake, 2014, Mitochondrial dysfunction and complications associated with diabetes, Biochimica et Biophysica Acta, 1840, 1404, 10.1016/j.bbagen.2013.11.007 Wallace, 2005, A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine, Annual Review of Genetics, 39, 359, 10.1146/annurev.genet.39.110304.095751 Chaturvedi, 2013, Mitochondrial diseases of the brain, Free Radical Biology and Medicine, 63, 1, 10.1016/j.freeradbiomed.2013.03.018 Dexter, 2013, Parkinson disease: from pathology to molecular disease mechanisms, Free Radical Biology and Medicine, 62, 132, 10.1016/j.freeradbiomed.2013.01.018 Purohit, 2009, Molecular mechanisms of alcoholic fatty liver, Alcoholism, Clinical and Experimental Research, 33, 191, 10.1111/j.1530-0277.2008.00827.x Gao, 2011, Alcoholic liver disease: pathogenesis and new therapeutic targets, Gastroenterology, 141, 1572, 10.1053/j.gastro.2011.09.002 Barnes, 2014, Innate immunity and cell death in alcoholic liver disease: role of cytochrome P4502E1, Redox Biology, 2, 929, 10.1016/j.redox.2014.07.007 Powell, 2005, Temporal correlation of pathology and DNA damage with gene expression in a choline-deficient model of rat liver injury, Hepatology (Baltimore, Md.), 42, 1137, 10.1002/hep.20910 Baffy, 2012, Hepatocellular carcinoma in non-alcoholic fatty liver disease: an emerging menace, Journal of Hepatology, 56, 1384, 10.1016/j.jhep.2011.10.027 Cover, 2005, Peroxynitrite-induced mitochondrial and endonuclease-mediated nuclear DNA damage in acetaminophen hepatotoxicity, Journal of Pharmacology and Experimental Therapeutics, 315, 879, 10.1124/jpet.105.088898 Jaeschke, 2012, Oxidant stress, mitochondria, and cell death mechanisms in drug-induced liver injury: lessons learned from acetaminophen hepatotoxicity, Drug Metabolism Reviews, 44, 88, 10.3109/03602532.2011.602688 Han, 2013, Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria, Trends in Pharmacological Sciences, 34, 243, 10.1016/j.tips.2013.01.009 Ribeiro, 2014, Mitochondria: the gateway for tamoxifen-induced liver injury, Toxicology, 323, 10, 10.1016/j.tox.2014.05.009 Banerjee, 2013, Zidovudine (AZT) and hepatic lipid accumulation: implication of inflammation, oxidative and endoplasmic reticulum stress mediators, PloS One, 8, e76850, 10.1371/journal.pone.0076850 Li, 2012, Mitochondrial dysfunction induced by sertraline, an antidepressant agent, Toxicological Sciences: an Official Journal of the Society of Toxicology, 127, 582, 10.1093/toxsci/kfs100 Pessayre, 2012, Central role of mitochondria in drug-induced liver injury, Drug Metabolism Reviews, 44, 34, 10.3109/03602532.2011.604086 Yuan, 2013, Mechanisms of drug-induced liver injury, Clinics in Liver Disease, 17, 507, 10.1016/j.cld.2013.07.002 Song, 2013, Increased nitroxidative stress promotes mitochondrial dysfunction in alcoholic and nonalcoholic fatty liver disease, Oxidative Medicine and Cellular Longevity, 2013, 781050, 10.1155/2013/781050 Abdelmegeed, 2014, Functional roles of protein nitration in acute and chronic liver diseases, Oxidative Medicine and Cellular Longevity, 2014, 1, 10.1155/2014/149627 Rhee, 2006, Cell signaling. H2O2, a necessary evil for cell signaling, Science (New York, N.Y.), 312, 1882, 10.1126/science.1130481 Hamanaka, 2010, Mitochondrial reactive oxygen species regulate cellular signaling and dictate biological outcomes, Trends in Biochemical Sciences, 35, 505, 10.1016/j.tibs.2010.04.002 Von Montfort, 2012, Mitochondrial GSH determines the toxic or therapeutic potential of superoxide scavenging in steatohepatitis, Journal of Hepatology, 57, 852, 10.1016/j.jhep.2012.05.024 Bastidas, 2013, Influence of N-myristylation and ligand binding on the flexibility of the catalytic subunit of protein kinase A, Biochemistry, 52, 6368, 10.1021/bi400575k Nadolski, 2007, Protein lipidation, FEBS Journal, 274, 5202, 10.1111/j.1742-4658.2007.06056.x Song, 2010, A simple method to systematically study oxidatively modified proteins in biological samples and its applications, Methods in Enzymology, 473, 251, 10.1016/S0076-6879(10)73013-5 Moon, 2006, Inactivation of oxidized and S-nitrosylated mitochondrial proteins in alcoholic fatty liver of rats, Hepatology (Baltimore, Md.), 44, 1218, 10.1002/hep.21372 Kim, 2006, Increased oxidation and degradation of cytosolic proteins in alcohol-exposed mouse liver and hepatoma cells, Proteomics, 6, 1250, 10.1002/pmic.200500447 Bai, 2001, Adenovirus-mediated overexpression of catalase in the cytosolic or mitochondrial compartment protects against cytochrome P450 2E1-dependent toxicity in HepG2 cells, Journal of Biological Chemistry, 276, 4315, 10.1074/jbc.M008895200 Suh, 2004, Identification of oxidized mitochondrial proteins in alcohol-exposed human hepatoma cells and mouse liver, Proteomics, 4, 3401, 10.1002/pmic.200400971 Moon, 2008, Oxidative inactivation of key mitochondrial proteins leads to dysfunction and injury in hepatic ischemia reperfusion, Gastroenterology, 135, 1344, 10.1053/j.gastro.2008.06.048 Moon, 2008, Mechanism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-mediated mitochondrial dysfunction in rat liver, Proteomics, 8, 3906, 10.1002/pmic.200800215 Pagliarini, 2008, A mitochondrial protein compendium elucidates complex I disease biology, Cell, 134, 112, 10.1016/j.cell.2008.06.016 Calvo, 2010, The mitochondrial proteome and human disease, Annual Review of Genomics and Human Genetics, 11, 25, 10.1146/annurev-genom-082509-141720 Song, 2011, Post-translational modifications of mitochondrial aldehyde dehydrogenase and biomedical implications, Journal of Proteomics, 74, 2691, 10.1016/j.jprot.2011.05.013 Moon, 2005, Inhibition of mitochondrial aldehyde dehydrogenase by nitric oxide-mediated S-nitrosylation, FEBS Letters, 579, 6115, 10.1016/j.febslet.2005.09.082 Venkatraman, 2004, Oxidative modification of hepatic mitochondria protein thiols: effect of chronic alcohol consumption, American Journal of Physiology. Gastrointestinal and Liver Physiology, 286, G521, 10.1152/ajpgi.00399.2003 Venkatraman, 2004, Modification of the mitochondrial proteome in response to the stress of ethanol-dependent hepatotoxicity, Journal of Biological Chemistry, 279, 22092, 10.1074/jbc.M402245200 Hartley, 1995, The hepatocellular metabolism of 4-hydroxynonenal by alcohol dehydrogenase, aldehyde dehydrogenase, and glutathione S-transferase, Archives of Biochemistry and Biophysics, 316, 197, 10.1006/abbi.1995.1028 Bae, 2011, Concerted action of sulfiredoxin and peroxiredoxin I protects against alcohol-induced oxidative injury in mouse liver, Hepatology (Baltimore, Md.), 53, 945, 10.1002/hep.24104 Rhee, 2012, Peroxiredoxin functions as a peroxidase and a regulator and sensor of local peroxides, Journal of Biological Chemistry, 287, 4403, 10.1074/jbc.R111.283432 Rhee, 2011, Multiple functions of peroxiredoxins: peroxidases, sensors and regulators of the intracellular messenger H2O2, and protein chaperones, Antioxidants and Redox Signaling, 15, 781, 10.1089/ars.2010.3393 Jo, 2001, Control of mitochondrial redox balance and cellular defense against oxidative damage by mitochondrial NADP+-dependent isocitrate dehydrogenase, Journal of Biological Chemistry, 276, 16168, 10.1074/jbc.M010120200 Lee, 2002, Cytosolic NADP(+)-dependent isocitrate dehydrogenase status modulates oxidative damage to cells, Free Radical Biology and Medicine, 32, 1185, 10.1016/S0891-5849(02)00815-8 Yang, 2002, Inactivation of NADP(+)-dependent isocitrate dehydrogenase by nitric oxide, Free Radical Biology and Medicine, 33, 927, 10.1016/S0891-5849(02)00981-4 Lee, 2003, Inactivation of NADP+-dependent isocitrate dehydrogenase by peroxynitrite. Implications for cytotoxicity and alcohol-induced liver injury, Journal of Biological Chemistry, 278, 51360, 10.1074/jbc.M302332200 Laval, 1994, Inhibition by nitric oxide of the repair protein, O6-methylguanine-DNA-methyltransferase, Carcinogenesis, 15, 443, 10.1093/carcin/15.3.443 Marinho, 2014, Hydrogen peroxide sensing, signaling and regulation of transcription factors, Redox Biology, 2, 535, 10.1016/j.redox.2014.02.006 Cohen, 2011, Redox signaling and the innate immune system in alcoholic liver disease, Antioxidants and Redox Signaling, 15, 523, 10.1089/ars.2010.3746 Nath, 2012, Hypoxia and hypoxia inducible factors: diverse roles in liver diseases, Hepatology (Baltimore, Md.), 55, 622, 10.1002/hep.25497 Zelickson, 2011, Nitric oxide and hypoxia exacerbate alcohol-induced mitochondrial dysfunction in hepatocytes, Biochimica et Biophysica Acta, 1807, 1573, 10.1016/j.bbabio.2011.09.011 Wang, 2013, Cytochrome P450 2E1 potentiates ethanol induction of hypoxia and HIF-1α in vivo, Free Radical Biology and Medicine, 63, 175, 10.1016/j.freeradbiomed.2013.05.009 Zhou, 2013, Long-term binge and escalating ethanol exposure causes necroinflammation and fibrosis in rat liver, Alcoholism, Clinical and Experimental Research, 37, 213, 10.1111/j.1530-0277.2012.01936.x Yun, 2014, Binge alcohol promotes hypoxic liver injury through CYP2E1-HIF1a-dependent apoptosis pathway in mice and humans, Free Radical Biology and Medicine, 77, 183, 10.1016/j.freeradbiomed.2014.08.030 Gong, 2006, Nrf2 is increased by CYP2E1 in rodent liver and HepG2 cells and protects against oxidative stress caused by CYP2E1, Hepatology (Baltimore, Md.), 43, 144, 10.1002/hep.21004 Wang, 2014, Nuclear factor (erythroid-derived 2)-like 2 activation-induced hepatic very-low-density lipoprotein receptor overexpression in response to oxidative stress contributes to alcoholic liver disease in mice, Hepatology (Baltimore, Md.), 59, 1381, 10.1002/hep.26912 Kathirvel, 2010, Oxidative stress and regulation of anti-oxidant enzymes in cytochrome P4502E1 transgenic mouse model of non-alcoholic fatty liver, Journal of Gastroenterology and Hepatology, 25, 1136, 10.1111/j.1440-1746.2009.06196.x Xu, 2011, Upregulation of Nrf2 expression in non-alcoholic fatty liver and steatohepatitis, Hepato-Gastroenterology, 58, 2077 Niture, 2014, Regulation of Nrf2-an update, Free Radical Biology and Medicine, 66, 36, 10.1016/j.freeradbiomed.2013.02.008 Grek, 2013, Causes and consequences of cysteine S-glutathionylation, Journal of Biological Chemistry, 288, 26497, 10.1074/jbc.R113.461368 Gould, 2013, Regulation of protein function and signaling by reversible cysteine S-nitrosylation, Journal of Biological Chemistry, 288, 26473, 10.1074/jbc.R113.460261 Sun, 2007, Preconditioning results in S-nitrosylation of proteins involved in regulation of mitochondrial energetics and calcium transport, Circulation Research, 101, 1155, 10.1161/CIRCRESAHA.107.155879 Kohr, 2011, Simultaneous measurement of protein oxidation and S-nitrosylation during preconditioning and ischemia/reperfusion injury with resin-assisted capture, Circulation Research, 108, 418, 10.1161/CIRCRESAHA.110.232173 Murphy, 2012, S-nitrosylation: a radical way to protect the heart, Journal of Molecular and Cellular Cardiology, 52, 568, 10.1016/j.yjmcc.2011.08.021 Mailloux, 2014, Redox regulation of mitochondrial function with emphasis on cysteine oxidation reactions, Redox Biology, 2, 123, 10.1016/j.redox.2013.12.011 Lu, 2014, The thioredoxin antioxidant system, Free Radical Biology and Medicine, 66, 75, 10.1016/j.freeradbiomed.2013.07.036 Pastore, 2012, S-glutathionylation signaling in cell biology: progress and prospects, European Journal of Pharmaceutical Sciences: Official Journal of the European Federation for Pharmaceutical Sciences, 46, 279, 10.1016/j.ejps.2012.03.010 Calcerrada, 2011, Nitric oxide-derived oxidants with a focus on peroxynitrite: molecular targets, cellular responses and therapeutic implications, Current Pharmaceutical Design, 17, 3905, 10.2174/138161211798357719 Brenner, 2013, Decoding cell death signals in liver inflammation, Journal of Hepatology, 59, 583, 10.1016/j.jhep.2013.03.033 Radi, 1991, Peroxynitrite oxidation of sulfhydryls. The cytotoxic potential of superoxide and nitric oxide, Journal of Biological Chemistry, 266, 4244, 10.1016/S0021-9258(20)64313-7 Wan, 2004, Acetoaminophen-induced accumulation of 8-oxodeoxyguanosine through reduction of Ogg1 DNA repair enzyme in C6 glioma cells, Experimental and Molecular Medicine, 36, 71, 10.1038/emm.2004.10 Begriche, 2006, Mitochondrial dysfunction in Nash: causes, consequences and possible means to prevent it, Mitochondrion, 6, 1, 10.1016/j.mito.2005.10.004 Elfering, 2004, Aspects, mechanism, and biological relevance of mitochondrial protein nitration sustained by mitochondrial nitric oxide synthase, American Journal of Physiology: Heart and Circulatory Physiology, 286, H22 Pickering, 2012, Degradation of damaged proteins: the main function of the 20S proteasome, Progress in Molecular Biology and Translational Science, 109, 227, 10.1016/B978-0-12-397863-9.00006-7 Wallace, 2008, Mitochondrial off targets of drug therapy, Trends in Pharmacological Sciences, 29, 361, 10.1016/j.tips.2008.04.001 Chandra, 2011, Genetic insights into OXPHOS defect and its role in cancer, Biochimica et Biophysica Acta, 1807, 620, 10.1016/j.bbabio.2010.10.023 Fromenty, 1997, Impaired mitochondrial function in microvesicular steatosis. Effects of drugs, ethanol, hormones and cytokines, Journal of Hepatology, 26, 43, 10.1016/S0168-8278(97)80496-5 Song, 2010, Mechanisms of MDMA (ecstasy)-induced oxidative stress, mitochondrial dysfunction, and organ damage, Current Pharmaceutical Biotechnology, 11, 434, 10.2174/138920110791591436 McKim, 2003, Inducible nitric oxide synthase is required in alcohol-induced liver injury: studies with knockout mice, Gastroenterology, 125, 1834, 10.1053/j.gastro.2003.08.030 Venkatraman, 2003, Chronic alcohol consumption increases the sensitivity of rat liver mitochondrial respiration to inhibition by nitric oxide, Hepatology (Baltimore, Md.), 38, 141, 10.1053/jhep.2003.50293 Venkatraman, 2004, The role of iNOS in alcohol-dependent hepatotoxicity and mitochondrial dysfunction in mice, Hepatology (Baltimore, Md.), 40, 565, 10.1002/hep.20326 Mantena, 2009, High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo, Biochemical Journal, 417, 183, 10.1042/BJ20080868 Spruss, 2011, Role of the inducible nitric oxide synthase in the onset of fructose-induced steatosis in mice, Antioxidants and Redox Signaling, 14, 2121, 10.1089/ars.2010.3263 Hinson, 1998, Nitrotyrosine-protein adducts in hepatic centrilobular areas following toxic doses of acetaminophen in mice, Chemical Research in Toxicology, 11, 604, 10.1021/tx9800349 Knight, 2002, Peroxynitrite is a critical mediator of acetaminophen hepatotoxicity in murine livers: protection by glutathione, Journal of Pharmacology and Experimental Therapeutics, 303, 468, 10.1124/jpet.102.038968 Abdelmegeed, 2010, Role of cytochrome P450 2E1 in protein nitration and ubiquitin-mediated degradation during acetaminophen toxicity, Biochemical Pharmacology, 79, 57, 10.1016/j.bcp.2009.07.016 Abdelmegeed, 2013, Robust protein nitration contributes to acetaminophen-induced mitochondrial dysfunction and acute liver injury, Free Radical Biology and Medicine, 60, 211, 10.1016/j.freeradbiomed.2013.02.018 Yun, 2013, A novel upregulation of glutathione peroxidase 1 by knockout of liver-regenerating protein Reg3β aggravates acetaminophen-induced hepatic protein nitration, Free Radical Biology and Medicine, 65, 291, 10.1016/j.freeradbiomed.2013.06.034 Yoo, 2011, Lack of PPARα exacerbates lipopolysaccharide-induced liver toxicity through STAT1 inflammatory signaling and increased oxidative/nitrosative stress, Toxicology Letters, 202, 23, 10.1016/j.toxlet.2011.01.013 Nuriel, 2011, Protein nitrotryptophan: formation, significance and identification, Journal of Proteomics, 74, 2300, 10.1016/j.jprot.2011.05.032 Bregere, 2008, Detection and characterization of in vivo nitration and oxidation of tryptophan residues in proteins, Methods in Enzymology, 441, 339, 10.1016/S0076-6879(08)01219-6 Yamakura, 2010, Post-translational modifications of superoxide dismutase, Biochimica et Biophysica Acta, 1804, 318, 10.1016/j.bbapap.2009.10.010 Ron, 2013, Signaling pathways mediating alcohol effects, Current Topics in Behavioral Neuroscience, 13, 87, 10.1007/978-3-642-28720-6_161 Sid, 2013, Role of AMPK activation in oxidative cell damage: Implications for alcohol-induced liver disease, Biochemical Pharmacology, 86, 200, 10.1016/j.bcp.2013.05.007 Son, 2013, Reactive oxygen species in the activation of MAP kinases, Methods in Enzymology, 528, 27, 10.1016/B978-0-12-405881-1.00002-1 Theodosiou, 2002, MAP kinase phosphatases, Genome Biology, 3, 10.1186/gb-2002-3-7-reviews3009 Kamata, 2005, Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases, Cell, 120, 649, 10.1016/j.cell.2004.12.041 Heneberg, 2005, Regulation of cys-based protein tyrosine phosphatases via reactive oxygen and nitrogen species in mast cells and basophils, Current Medicinal Chemistry, 12, 1859, 10.2174/0929867054546636 Geraldes, 2009, Activation of PKC-delta and SHP-1 by hyperglycemia causes vascular cell apoptosis and diabetic retinopathy, Nature Medicine, 15, 1298, 10.1038/nm.2052 Ryer, 2005, Protein kinase C delta induces apoptosis of vascular smooth muscle cells through induction of the tumor suppressor p53 by both p38-dependent and p38-independent mechanisms, Journal of Biological Chemistry, 280, 35310, 10.1074/jbc.M507187200 Gonzalez-Guerrico, 2005, Phorbol ester-induced apoptosis in prostate cancer cells via autocrine activation of the extrinsic apoptotic cascade: a key role for protein kinase C delta, Journal of Biological Chemistry, 280, 38982, 10.1074/jbc.M506767200 Kwon, 2004, Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors, Proceedings of the National Academy of Sciences of the United States of America, 101, 16419, 10.1073/pnas.0407396101 Lee, 2005, Pro- and anti-apoptotic roles of c-Jun N-terminal kinase (JNK) in ethanol and acetaldehyde exposed rat hepatocytes, European Journal of Pharmacology, 508, 31, 10.1016/j.ejphar.2004.12.006 Yang, 2012, Cytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver, Free Radical Biology and Medicine, 53, 1170, 10.1016/j.freeradbiomed.2012.06.029 Bae, 2001, Acetaminophen induces apoptosis of C6 glioma cells by activating the c-Jun NH(2)-terminal protein kinase-related cell death pathway, Molecular Pharmacology, 60, 847 Gunawan, 2006, C-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity, Gastroenterology, 131, 165, 10.1053/j.gastro.2006.03.045 Henderson, 2007, Critical role of c-jun (NH2) terminal kinase in paracetamol-induced acute liver failure, Gut, 56, 982, 10.1136/gut.2006.104372 Hanawa, 2008, Role of JNK translocation to mitochondria leading to inhibition of mitochondria bioenergetics in acetaminophen-induced liver injury, Journal of Biological Chemistry, 283, 13565, 10.1074/jbc.M708916200 Win, 2011, C-Jun N-terminal kinase (JNK)-dependent acute liver injury from acetaminophen or tumor necrosis factor (TNF) requires mitochondrial sab protein expression in mice, Journal of Biological Chemistry, 286, 35071, 10.1074/jbc.M111.276089 Wu, 2003, Role of p38 MAPK in CYP2E1-dependent arachidonic acid toxicity, Journal of Biological Chemistry, 278, 1115, 10.1074/jbc.M207856200 Soh, 2000, Selective activation of the c-Jun N-terminal protein kinase pathway during 4-hydroxynonenal-induced apoptosis of PC12 cells, Molecular Pharmacology, 58, 535, 10.1124/mol.58.3.535 Solinas, 2006, Saturated fatty acids inhibit induction of insulin gene transcription by JNK-mediated phosphorylation of insulin-receptor substrates, Proceedings of the National Academy of Sciences of the United States of America, 103, 16454, 10.1073/pnas.0607626103 Bae, 2003, Critical role of c-Jun N-terminal protein kinase activation in troglitazone-induced apoptosis of human HepG2 hepatoma cells, Molecular Pharmacology, 63, 401, 10.1124/mol.63.2.401 Schattenberg, 2005, Hepatocyte CYP2E1 overexpression and steatohepatitis lead to impaired hepatic insulin signaling, Journal of Biological Chemistry, 280, 9887, 10.1074/jbc.M410310200 Schattenberg, 2006, JNK1 but not JNK2 promotes the development of steatohepatitis in mice, Hepatology (Baltimore, Md.), 43, 163, 10.1002/hep.20999 Tuncman, 2006, Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance, Proceedings of the National Academy of Sciences of the United States of America, 103, 10741, 10.1073/pnas.0603509103 Gao, 2011, Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun N-terminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity, Journal of Biological Chemistry, 286, 22227, 10.1074/jbc.M111.228874 Uehara, 2005, JNK mediates hepatic ischemia reperfusion injury, Journal of Hepatology, 42, 850, 10.1016/j.jhep.2005.01.030 Seki, 2012, A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches, Gastroenterology, 143, 307, 10.1053/j.gastro.2012.06.004 Wang, 2011, Hepatotoxicity mediated by pyrazole (cytochrome P450 2E1) plus tumor necrosis factor alpha treatment occurs in c-Jun N-terminal kinase 2-/- but not in c-Jun N-terminal kinase 1−/− mice, Hepatology (Baltimore, Md.), 54, 1753, 10.1002/hep.24540 Son, 2011, Mitogen-activated protein kinases and reactive oxygen species: how can ROS activate MAPK pathways?, Journal of Signal Transduction, 2011, 792639, 10.1155/2011/792639 Kim, 2006, JNK- and p38 kinase-mediated phosphorylation of Bax leads to its activation and mitochondrial translocation and to apoptosis of human hepatoma HepG2 cells, Journal of Biological Chemistry, 281, 21256, 10.1074/jbc.M510644200 Kharbanda, 2000, Translocation of SAPK/JNK to mitochondria and interaction with Bcl-x(L) in response to DNA damage, Journal of Biological Chemistry, 275, 322, 10.1074/jbc.275.1.322 Xie, 2014, Mechanisms of acetaminophen-induced cell death in primary human hepatocytes, Toxicology and Applied Pharmacology, 279, 266, 10.1016/j.taap.2014.05.010 Ferramosca, 2013, Biogenesis of mitochondrial carrier proteins: molecular mechanisms of import into mitochondria, Biochimica et Biophysica Acta, 1833, 494, 10.1016/j.bbamcr.2012.11.014 Moon, 2010, Inhibition of hepatic mitochondrial aldehyde dehydrogenase by carbon tetrachloride through JNK-mediated phosphorylation, Free Radical Biology and Medicine, 48, 391, 10.1016/j.freeradbiomed.2009.11.008 Win, 2014, JNK interaction with sab mediates ER stress induced inhibition of mitochondrial respiration and cell death, Cell Death and Disease, 5, e989, 10.1038/cddis.2013.522 Schroeter, 2003, C-Jun N-terminal kinase (JNK)-mediated modulation of brain mitochondria function: new target proteins for JNK signalling in mitochondrion-dependent apoptosis, Biochemical Journal, 372, 359, 10.1042/bj20030201 Hardie, 2014, AMP-activated protein kinase: maintaining energy homeostasis at the cellular and whole-body levels, Annual Review of Nutrition, 34, 31, 10.1146/annurev-nutr-071812-161148 You, 2004, The role of AMP-activated protein kinase in the action of ethanol in the liver, Gastroenterology, 127, 1798, 10.1053/j.gastro.2004.09.049 Singhal, 2013, RLIP76 protein knockdown attenuates obesity due to a high-fat diet, Journal of Biological Chemistry, 288, 23394, 10.1074/jbc.M113.480194 Saberi, 2014, Protein kinase C (PKC) participates in acetaminophen hepatotoxicity through c-jun-N-terminal kinase (JNK)-dependent and -independent signaling pathways, Hepatology (Baltimore, Md.), 59, 1543, 10.1002/hep.26625 Sun, 2011, Circadian epigenomic remodeling and hepatic lipogenesis: lessons from HDAC3, Cold Spring Harbor Symposia on Quantitative Biology, 76, 49, 10.1101/sqb.2011.76.011494 Kim, 2006, Substrate and functional diversity of lysine acetylation revealed by a proteomics survey, Molecular Cell, 23, 607, 10.1016/j.molcel.2006.06.026 You, 2008, Involvement of mammalian sirtuin 1 in the action of ethanol in the liver, American Journal of Physiology: Gastrointestinal and Liver Physiology, 294, G892 Lieber, 2008, Effect of chronic alcohol consumption on hepatic SIRT1 and PGC-1alpha in rats, Biochemical and Biophysical Research Communications, 370, 44, 10.1016/j.bbrc.2008.03.005 Picklo, 2008, Ethanol intoxication increases hepatic N-lysyl protein acetylation, Biochemical and Biophysical Research Communications, 376, 615, 10.1016/j.bbrc.2008.09.039 Shepard, 2010, Chronic ethanol consumption induces global hepatic protein hyperacetylation, Alcoholism, Clinical and Experimental Research, 34, 280, 10.1111/j.1530-0277.2009.01091.x Kendrick, 2011, Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation, Biochemical Journal, 433, 505, 10.1042/BJ20100791 Hirschey, 2011, SIRT3 deficiency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome, Molecular Cell, 44, 177, 10.1016/j.molcel.2011.07.019 Valdecantos, 2012, Lipoic acid improves mitochondrial function in nonalcoholic steatosis through the stimulation of sirtuin 1 and sirtuin 3, Obesity (Silver Spring, Md.), 20, 1974, 10.1038/oby.2012.32 Lieber, 2008, Alcohol alters hepatic FoxO1, p53, and mitochondrial SIRT5 deacetylation function, Biochemical and Biophysical Research Communications, 373, 246, 10.1016/j.bbrc.2008.06.006 Shulga, 2010, Ethanol sensitizes mitochondria to the permeability transition by inhibiting deacetylation of cyclophilin-D mediated by sirtuin-3, Journal of Cell Science, 123, 4117, 10.1242/jcs.073502 Fritz, 2011, 4-hydroxynonenal inhibits SIRT3 via thiol-specific modification, Chemical Research in Toxicology, 24, 651, 10.1021/tx100355a Fritz, 2012, Mitochondrial acetylome analysis in a mouse model of alcohol-induced liver injury utilizing SIRT3 knockout mice, Journal of Proteome Research, 11, 1633, 10.1021/pr2008384 Fritz, 2013, Ethanol metabolism modifies hepatic protein acylation in mice, PloS One, 8, e75868, 10.1371/journal.pone.0075868 Hirschey, 2010, SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation, Nature, 464, 121, 10.1038/nature08778 Hirschey, 2011, SIRT3 regulates mitochondrial protein acetylation and intermediary metabolism, Cold Spring Harbor Symposia on Quantitative Biology, 76, 267, 10.1101/sqb.2011.76.010850 Yang, 2014, Resveratrol ameliorates hepatic metaflammation and inhibits NLRP3 inflammasome activation, Metabolism: Clinical and Experimental, 63, 693, 10.1016/j.metabol.2014.02.003 Wang, 2014, Novel insights of dietary polyphenols and obesity, Journal of Nutritional Biochemistry, 25, 1, 10.1016/j.jnutbio.2013.09.001 Still, 2013, Quantification of mitochondrial acetylation dynamics highlights prominent sites of metabolic regulation, Journal of Biological Chemistry, 288, 26209, 10.1074/jbc.M113.483396 Paik, 1970, Nonenzymatic acetylation of histones with acetyl-CoA, Biochimica et Biophysica Acta, 213, 513, 10.1016/0005-2787(70)90058-4 Ramponi, 1975, Nonenzymatic acetylation of histones with acetyl phosphate and acetyl adenylate, Biochemistry, 14, 2681, 10.1021/bi00683a018 Tanner, 1999, Catalytic mechanism and function of invariant glutamic acid 173 from the histone acetyltransferase GCN5 transcriptional coactivator, Journal of Biological Chemistry, 274, 18157, 10.1074/jbc.274.26.18157 French, 1993, Effect of ethanol on cytochrome P450 2E1 (CYP2E1), lipid peroxidation, and serum protein adduct formation in relation to liver pathology pathogenesis, Experimental and Molecular Pathology, 58, 61, 10.1006/exmp.1993.1006 Niemelä, 1998, Early alcoholic liver injury: formation of protein adducts with acetaldehyde and lipid peroxidation products, and expression of CYP2E1 and CYP3A, Alcoholism, Clinical and Experimental Research, 22, 2118, 10.1111/j.1530-0277.1998.tb05925.x Brooks, 2009, The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption, PLoS Medicine, 6, e50, 10.1371/journal.pmed.1000050 Yokoyama, 2001, Alcohol and aldehyde dehydrogenase gene polymorphisms and oropharyngolaryngeal, esophageal and stomach cancers in Japanese alcoholics, Carcinogenesis, 22, 433, 10.1093/carcin/22.3.433 Jaeschke, 2002, Mechanisms of hepatotoxicity, Toxicological Sciences: an Official Journal of the Society of Toxicology, 65, 166, 10.1093/toxsci/65.2.166 Galligan, 2012, Protein carbonylation in a murine model for early alcoholic liver disease, Chemical Research in Toxicology, 25, 1012, 10.1021/tx300002q Fritz, 2013, An overview of the chemistry and biology of reactive aldehydes, Free Radical Biology and Medicine, 59, 85, 10.1016/j.freeradbiomed.2012.06.025 Cohn, 1996, Chemical characterization of a protein-4-hydroxy-2-nonenal cross-link: immunochemical detection in mitochondria exposed to oxidative stress, Archives of Biochemistry and Biophysics, 328, 158, 10.1006/abbi.1996.0156 Niemelä, 1995, Sequential acetaldehyde production, lipid peroxidation, and fibrogenesis in micropig model of alcohol-induced liver disease, Hepatology (Baltimore, Md.), 22, 1208, 10.1016/0270-9139(95)90630-4 Li, 1997, Acetaldehyde-modified and 4-hydroxynonenal-modified proteins in the livers of rats with alcoholic liver disease, Hepatology (Baltimore, Md.), 26, 650, 10.1002/hep.510260317 Chen, 1999, Formation of 4-hydroxynonenal adducts with cytochrome c oxidase in rats following short-term ethanol intake, Hepatology (Baltimore, Md.), 29, 1792, 10.1002/hep.510290611 Doorn, 2006, Inhibition of human mitochondrial aldehyde dehydrogenase by 4-hydroxynon-2-enal and 4-oxonon-2-enal, Chemical Research in Toxicology, 19, 102, 10.1021/tx0501839 Carbone, 2005, Cysteine modification by lipid peroxidation products inhibits protein disulfide isomerase, Chemical Research in Toxicology, 18, 1324, 10.1021/tx050078z Galligan, 2014, Oxidative stress-mediated aldehyde adduction of GRP78 in a mouse model of alcoholic liver disease: functional independence of ATPase activity and chaperone function, Free Radical Biology and Medicine, 73, 411, 10.1016/j.freeradbiomed.2014.06.002 Backos, 2011, Posttranslational modification and regulation of glutamate-cysteine ligase by the α,β-unsaturated aldehyde 4-hydroxy-2-nonenal, Free Radical Biology and Medicine, 50, 14, 10.1016/j.freeradbiomed.2010.10.694 Sampey, 2007, Ethanol-induced modulation of hepatocellular extracellular signal-regulated kinase-1/2 activity via 4-hydroxynonenal, Journal of Biological Chemistry, 282, 1925, 10.1074/jbc.M610602200 Shearn, 2013, Increased carbonylation of the lipid phosphatase PTEN contributes to Akt2 activation in a murine model of early alcohol-induced steatosis, Free Radical Biology and Medicine, 65, 680, 10.1016/j.freeradbiomed.2013.07.011 Shearn, 2014, Identification of 5′ AMP-activated kinase as a target of reactive aldehydes during chronic ingestion of high concentrations of ethanol, Journal of Biological Chemistry, 289, 15449, 10.1074/jbc.M113.543942 Mottaran, 2002, Lipid peroxidation contributes to immune reactions associated with alcoholic liver disease, Free Radical Biology and Medicine, 32, 38, 10.1016/S0891-5849(01)00757-2 Jeong, 2000, Cytochrome P450 2E1 (CYP2E1)-dependent production of a 37-kDa acetaldehyde-protein adduct in the rat liver, Archives of Biochemistry and Biophysics, 384, 81, 10.1006/abbi.2000.2119 Bardag-Gorce, 2005, The effect of ethanol-induced CYP2E1 on proteasome activity: the role of 4-hydroxynonenal, Experimental and Molecular Pathology, 78, 109, 10.1016/j.yexmp.2004.10.005 Chen, 2001, Role of 4-hydroxynonenal in modification of cytochrome c oxidase in ischemia/reperfused rat heart, Journal of Molecular and Cellular Cardiology, 33, 1919, 10.1006/jmcc.2001.1454 Chavez, 2011, Site-specific proteomic analysis of lipoxidation adducts in cardiac mitochondria reveals chemical diversity of 2-alkenal adduction, Journal of Proteomics, 74, 2417, 10.1016/j.jprot.2011.03.031 Abdelmegeed, 2012, Critical role of cytochrome P450 2E1 (CYP2E1) in the development of high fat-induced non-alcoholic steatohepatitis, Journal of Hepatology, 57, 860, 10.1016/j.jhep.2012.05.019 Mali, 2014, Impairment of aldehyde dehydrogenase-2 by 4-hydroxy-2-nonenal adduct formation and cardiomyocyte hypertrophy in mice fed a high-fat diet and injected with low-dose streptozotocin, Experimental Biology and Medicine (Maywood, N.J.), 239, 610, 10.1177/1535370213520109 Chen, 2008, Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart, Science (New York, N.Y.), 321, 1493, 10.1126/science.1158554 Doser, 2009, Transgenic overexpression of aldehyde dehydrogenase-2 rescues chronic alcohol intake-induced myocardial hypertrophy and contractile dysfunction, Circulation, 119, 1941, 10.1161/CIRCULATIONAHA.108.823799 Zhang, 2014, Mitochondrial aldehyde dehydrogenase 2 accentuates aging-induced cardiac remodeling and contractile dysfunction: role of AMPK, Sirt1, and mitochondrial function, Free Radical Biology and Medicine, 71, 208, 10.1016/j.freeradbiomed.2014.03.018 Daffu, 2013, Radical roles for RAGE in the pathogenesis of oxidative stress in cardiovascular diseases and beyond, International Journal of Molecular Sciences, 14, 19891, 10.3390/ijms141019891 Ott, 2014, Role of advanced glycation end products in cellular signaling, Redox Biology, 2, 411, 10.1016/j.redox.2013.12.016 Niforou, 2014, Molecular chaperones and proteostasis regulation during redox imbalance, Redox Biology, 2, 323, 10.1016/j.redox.2014.01.017 Hayashi, 2013, Acetaldehyde-derived advanced glycation end-products promote alcoholic liver disease, PloS One, 8, e70034, 10.1371/journal.pone.0070034 Ahmed, 2005, Increased protein glycation in cirrhosis and therapeutic strategies to prevent it, Annals of the New York Academy of Sciences, 1043, 718, 10.1196/annals.1333.083 Baba, 2011, Aldose reductase (AKR1B3) regulates the accumulation of advanced glycosylation end products (AGEs) and the expression of AGE receptor (RAGE), Chemico-Biological Interactions, 191, 357, 10.1016/j.cbi.2011.01.024 Jiang, 2013, Advanced glycation endproducts induce fibrogenic activity in nonalcoholic steatohepatitis by modulating TNF-α-converting enzyme activity in mice, Hepatology (Baltimore, Md.), 58, 1339, 10.1002/hep.26491 Bakala, 2013, Differential expression and glycative damage affect specific mitochondrial proteins with aging in rat liver, Biochimica et Biophysica Acta, 1832, 2057, 10.1016/j.bbadis.2013.07.015 Takeuchi, 2005, Cytotoxicity of acetaldehyde-derived advanced glycation end-products (AA-AGE) in alcoholic-induced neuronal degeneration, Alcoholism, Clinical and Experimental Research, 29, 220S, 10.1097/01.alc.0000190657.97988.c7 Byun, 2014, Microglial AGE-albumin is critical in promoting alcohol-induced neurodegeneration in Rats and humans, PloS One, 9, e104699, 10.1371/journal.pone.0104699 Vetreno, 2013, Increased receptor for advanced glycation end product expression in the human alcoholic prefrontal cortex is linked to adolescent drinking, Neurobiology of Disease, 59, 52, 10.1016/j.nbd.2013.07.002 Ahn, 2008, Human microglial cells synthesize albumin in brain, PloS One, 3, e2829, 10.1371/journal.pone.0002829 Byun, 2012, Induction of neuronal death by microglial AGE-albumin: implications for Alzheimer's disease, PloS One, 7, e37917, 10.1371/journal.pone.0037917 Albano, 1996, Role of cytochrome P4502E1-dependent formation of hydroxyethyl free radical in the development of liver damage in rats intragastrically fed with ethanol, Hepatology (Baltimore, Md.), 23, 155, 10.1002/hep.510230121 Clot, 1996, Cytochrome P4502E1 hydroxyethyl radical adducts as the major antigen in autoantibody formation among alcoholics, Gastroenterology, 111, 206, 10.1053/gast.1996.v111.pm8698201 Cheshchevik, 2012, Rat liver mitochondrial damage under acute or chronic carbon tetrachloride-induced intoxication: protection by melatonin and cranberry flavonoids, Toxicology and Applied Pharmacology, 261, 271, 10.1016/j.taap.2012.04.007 Kim, 2014, New insights into the mechanisms of polyphenols beyond antioxidant properties; lessons from the green tea polyphenol, epigallocatechin 3-gallate, Redox Biology, 2, 187, 10.1016/j.redox.2013.12.022 Zou, 2014, Mitochondrial dysfunction in obesity-associated nonalcoholic fatty liver disease: the protective effects of pomegranate with its active component punicalagin, Antioxidants and Redox Signaling, 10.1089/ars.2013.5538 Pallauf, 2013, Nutrition and healthy ageing: calorie restriction or polyphenol-rich “MediterrAsian” diet?, Oxidative Medicine and Cellular Longevity, 2013, 707421, 10.1155/2013/707421 Davinelli, 2012, Pleiotropic protective effects of phytochemicals in Alzheimer's disease, Oxidative Medicine and Cellular Longevity, 2012, 386527, 10.1155/2012/386527 Basli, 2012, Wine polyphenols: potential agents in neuroprotection, oxid, Medicine, 2012, 805762 Rodrigues, 2013, Drug-delivery systems of green tea catechins for improved stability and bioavailability, Current Medicinal Chemistry, 20, 4744, 10.2174/09298673113209990158 Bailey, 2006, S-adenosylmethionine prevents chronic alcohol-induced mitochondrial dysfunction in the rat liver, American Journal of Physiology: Gastrointestinal and Liver Physiology, 291, G857 Andringa, 2010, Analysis of the liver mitochondrial proteome in response to ethanol and S-adenosylmethionine treatments: novel molecular targets of disease and hepatoprotection, American Journal of Physiology: Gastrointestinal and Liver Physiology, 298, G732 Kharbanda, 2012, Betaine treatment attenuates chronic ethanol-induced hepatic steatosis and alterations to the mitochondrial respiratory chain proteome, International Journal of Hepatology, 2012, 962183, 10.1155/2012/962183 Santamaria, 2003, Functional proteomics of nonalcoholic steatohepatitis: mitochondrial proteins as targets of S-adenosylmethionine, Proceedings of the National Academy of Sciences of the United States of America, 100, 3065, 10.1073/pnas.0536625100 Caballero, 2010, Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: impact on mitochondrial S-adenosyl-l-methionine and glutathione, Journal of Biological Chemistry, 285, 18528, 10.1074/jbc.M109.099333 Basaranoglu, 2013, From fatty liver to fibrosis: a tale of “second hit”, World Journal of Gastroenterology: WJG, 19, 1158, 10.3748/wjg.v19.i8.1158 Zhao, 2004, Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury, Journal of Biological Chemistry, 279, 34682, 10.1074/jbc.M402999200 Sheu, 2006, Targeting antioxidants to mitochondria: a new therapeutic direction, Biochimica et Biophysica Acta, 1762, 256, 10.1016/j.bbadis.2005.10.007 Szeto, 2006, Cell-permeable, mitochondrial-targeted, peptide antioxidants, AAPS Journal, 8, E277, 10.1007/BF02854898 Melov, 2001, Lifespan extension and rescue of spongiform encephalopathy in superoxide dismutase 2 nullizygous mice treated with superoxide dismutase-catalase mimetics, Journal of Neuroscience, 21, 8348, 10.1523/JNEUROSCI.21-21-08348.2001 Reily, 2013, Mitochondrially targeted compounds and their impact on cellular bioenergetics, Redox Biology, 1, 86, 10.1016/j.redox.2012.11.009 Murphy, 2014, Antioxidants as therapies: can we improve on nature?, Free Radical Biology and Medicine, 66, 20, 10.1016/j.freeradbiomed.2013.04.010 Jauslin, 2003, Mitochondria-targeted antioxidants protect Friedreich ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants, FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology, 17, 1972, 10.1096/fj.03-0240fje Chacko, 2010, Prevention of diabetic nephropathy in Ins2(+/)-(AkitaJ) mice by the mitochondria-targeted therapy MitoQ, Biochemical Journal, 432, 9, 10.1042/BJ20100308 Mukhopadhyay, 2012, Mitochondrial-targeted antioxidants represent a promising approach for prevention of cisplatin-induced nephropathy, Free Radical Biology and Medicine, 52, 497, 10.1016/j.freeradbiomed.2011.11.001 Vergeade, 2010, Mitochondrial impairment contributes to cocaine-induced cardiac dysfunction: prevention by the targeted antioxidant MitoQ, Free Radical Biology and Medicine, 49, 748, 10.1016/j.freeradbiomed.2010.05.024 Mukhopadhyay, 2012, Mitochondrial reactive oxygen species generation triggers inflammatory response and tissue injury associated with hepatic ischemia-reperfusion: therapeutic potential of mitochondrially targeted antioxidants, Free Radical Biology and Medicine, 53, 1123, 10.1016/j.freeradbiomed.2012.05.036 Chacko, 2011, Mitochondria-targeted ubiquinone (MitoQ) decreases ethanol-dependent micro and macro hepatosteatosis, Hepatology (Baltimore, Md.), 54, 153, 10.1002/hep.24377 Gane, 2010, The mitochondria-targeted anti-oxidant mitoquinone decreases liver damage in a phase II study of hepatitis C patients, Liver International: Official Journal of the International Association for the Study of the Liver, 30, 1019, 10.1111/j.1478-3231.2010.02250.x Smith, 2010, Animal and human studies with the mitochondria-targeted antioxidant MitoQ, Annals of the New York Academy of Sciences, 1201, 96, 10.1111/j.1749-6632.2010.05627.x Zhong, 2010, The role of zinc deficiency in alcohol-induced intestinal barrier dysfunction, American Journal of Physiology. Gastrointestinal and Liver Physiology, 298, G625, 10.1152/ajpgi.00350.2009 Kirpich, 2012, The type of dietary fat modulates intestinal tight junction integrity, gut permeability, and hepatic Toll-like receptor expression in a mouse model of alcoholic liver disease, Alcoholism, Clinical and Experimental Research, 36, 835, 10.1111/j.1530-0277.2011.01673.x Dunagan, 2012, Acetaldehyde disrupts tight junctions in Caco-2 cell monolayers by a protein phosphatase 2A-dependent mechanism, American Journal of Physiology. Gastrointestinal and Liver Physiology, 303, G1356, 10.1152/ajpgi.00526.2011 Kirpich, 2013, Ethanol and dietary unsaturated fat (corn oil/linoleic acid enriched) cause intestinal inflammation and impaired intestinal barrier defense in mice chronically fed alcohol, Alcohol (Fayetteville, N.Y.), 47, 257, 10.1016/j.alcohol.2013.01.005 Ge, 2013, Milk osteopontin, a nutritional approach to prevent alcohol-induced liver injury, American Journal of Physiology. Gastrointestinal and Liver Physiology, 304, G929, 10.1152/ajpgi.00014.2013 Forsyth, 2013, Role for intestinal CYP2E1 in alcohol-induced circadian gene-mediated intestinal hyperpermeability, American Journal of Physiology: Gastrointestinal and Liver Physiology, 305, G185 Abdelmegeed, 2013, CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis, Free Radical Biology and Medicine, 65, 1238, 10.1016/j.freeradbiomed.2013.09.009 Cresci, 2014, Tributyrin supplementation protects mice from acute ethanol-induced gut injury, Alcoholism, Clinical and Experimental Research, 38, 1489, 10.1111/acer.12428 Spruss, 2009, Dietary fructose and intestinal barrier: potential risk factor in the pathogenesis of nonalcoholic fatty liver disease, Journal of Nutritional Biochemistry, 20, 657, 10.1016/j.jnutbio.2009.05.006 Spruss, 2012, Metformin protects against the development of fructose-induced steatosis in mice: role of the intestinal barrier function, Laboratory Investigation: a Journal of Technical Methods and Pathology, 92, 1020, 10.1038/labinvest.2012.75 Ritze, 2014, Lactobacillus rhamnosus GG protects against non-alcoholic fatty liver disease in mice, PloS One, 9, e80169, 10.1371/journal.pone.0080169