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BioMed Research International
Volume 2014, Article ID 498491, 20 pages
http://dx.doi.org/10.1155/2014/498491
Review Article

Autophagy in Alcohol-Induced Multiorgan Injury: Mechanisms and Potential Therapeutic Targets

1Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, MS 1018 3901 Rainbow Boulevard, Kansas City, KS 66160, USA
2Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, China

Received 4 May 2014; Accepted 29 June 2014; Published 17 July 2014

Academic Editor: Patrice Codogno

Copyright © 2014 Yuan Li et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. B. Gao and R. Bataller, “Alcoholic liver disease: pathogenesis and new therapeutic targets,” Gastroenterology, vol. 141, no. 5, pp. 1572–1585, 2011. View at Publisher · View at Google Scholar · View at Scopus
  2. I. Gukovsky, A. Lugea, M. Shahsahebi et al., “A rat model reproducing key pathological responses of alcoholic chronic pancreatitis,” The American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 294, no. 1, pp. G68–G79, 2007. View at Publisher · View at Google Scholar · View at Scopus
  3. H. Gu, F. Fortunato, F. Bergmann, M. W. Buchler, D. C. Whitcomb, and J. Werner, “Alcohol exacerbates LPS-induced fibrosis in subclinical acute pancreatitis,” American Journal of Pathology, vol. 183, pp. 1508–1517, 2013. View at Publisher · View at Google Scholar
  4. M. R. Piano and S. A. Phillips, “Alcoholic cardiomyopathy: pathophysiologic insights,” Cardiovascular Toxicology, 2014. View at Publisher · View at Google Scholar
  5. J. Ren and L. E. Wold, “Mechanisms of alcoholic heart disease,” Therapeutic Advances in Cardiovascular Disease, vol. 2, no. 6, pp. 497–506, 2008. View at Publisher · View at Google Scholar · View at Scopus
  6. C. Harper, “The neuropathology of alcohol-related brain damage,” Alcohol and Alcoholism, vol. 44, no. 2, pp. 136–140, 2009. View at Publisher · View at Google Scholar · View at Scopus
  7. C. H. Lang, R. A. Frost, E. Svanberg, and T. C. Vary, “IGF-I/IGFBP-3 ameliorates alterations in protein synthesis, eIF4E availability, and myostatin in alcohol-fed rats,” The American Journal of Physiology: Endocrinology and Metabolism, vol. 286, no. 6, pp. E916–E926, 2004. View at Publisher · View at Google Scholar · View at Scopus
  8. D. Pruett, E. H. Waterman, and A. B. Caughey, “Fetal alcohol exposure: consequences, diagnosis, and treatment,” Obstetrical and Gynecological Survey, vol. 68, no. 1, pp. 62–69, 2013. View at Publisher · View at Google Scholar · View at Scopus
  9. D. B. Maurel, N. Boisseau, C. L. Benhamou, and C. Jaffre, “Alcohol and bone: review of dose effects and mechanisms,” Osteoporosis International, vol. 23, no. 1, pp. 1–16, 2012. View at Publisher · View at Google Scholar · View at Scopus
  10. P. E. Molina, C. McClain, D. Valla et al., “Molecular pathology and clinical aspects of alcohol-induced tissue injury,” Alcoholism: Clinical and Experimental Research, vol. 26, no. 1, pp. 120–128, 2002. View at Publisher · View at Google Scholar · View at Scopus
  11. Z. Xie and D. J. Klionsky, “Autophagosome formation: core machinery and adaptations,” Nature Cell Biology, vol. 9, no. 10, pp. 1102–1109, 2007. View at Publisher · View at Google Scholar · View at Scopus
  12. N. Mizushima, B. Levine, A. M. Cuervo, and D. J. Klionsky, “Autophagy fights disease through cellular self-digestion,” Nature, vol. 451, no. 7182, pp. 1069–1075, 2008. View at Publisher · View at Google Scholar · View at Scopus
  13. W. X. Ding, S. Manley, and H. M. Ni, “The emerging role of autophagy in alcoholic liver disease,” Experimental Biology and Medicine, vol. 236, no. 5, pp. 546–556, 2011. View at Publisher · View at Google Scholar · View at Scopus
  14. A. Dolganiuc, P. G. Thomes, W.-X. Ding, J. J. Lemasters, and T. M. Donohue, “Autophagy in alcohol-induced liver diseases,” Alcoholism: Clinical and Experimental Research, vol. 36, no. 8, pp. 1301–1308, 2012. View at Publisher · View at Google Scholar · View at Scopus
  15. M. J. Czaja, W. X. Ding, T. M. Donohue Jr. et al., “Functions of autophagy in normal and diseased liver,” Autophagy, vol. 9, no. 8, pp. 1131–1158, 2013. View at Publisher · View at Google Scholar · View at Scopus
  16. D. W. Crabb, M. Matsumoto, D. Chang, and M. You, “Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology,” Proceedings of the Nutrition Society, vol. 63, no. 1, pp. 49–63, 2004. View at Publisher · View at Google Scholar · View at Scopus
  17. C. C. Chen, R. B. Lu, Y. C. Chen et al., “Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism,” American Journal of Human Genetics, vol. 65, no. 3, pp. 795–807, 1999. View at Publisher · View at Google Scholar · View at Scopus
  18. C. S. Lieber, L. M. DeCarli, L. Feinman et al., “Effect of chronic alcohol consumption on ethanol and acetaldehyde metabolism,” Advances in Experimental Medicine and Biology, vol. 59, pp. 185–227, 1975. View at Publisher · View at Google Scholar · View at Scopus
  19. A. Vonlaufen, J. S. Wilson, R. C. Pirola, and M. V. Apte, “Role of alcohol metabolism in chronic pancreatitis,” Alcohol Research and Health, vol. 30, no. 1, pp. 48–54, 2007. View at Google Scholar · View at Scopus
  20. S. Zakhari, “Overview: how is alcohol metabolized by the body?” Alcohol Research & Health, vol. 29, no. 4, pp. 245–254, 2006. View at Google Scholar · View at Scopus
  21. Y. Lu and A. I. Cederbaum, “CYP2E1 and oxidative liver injury by alcohol,” Free Radical Biology and Medicine, vol. 44, no. 5, pp. 723–738, 2008. View at Publisher · View at Google Scholar · View at Scopus
  22. I. Zelner, J. N. Matlow, A. Natekar, and G. Koren, “Synthesis of fatty acid ethyl esters in mammalian tissues after ethanol exposure: a systematic review of the literature,” Drug Metabolism Reviews, vol. 45, no. 3, pp. 277–299, 2013. View at Publisher · View at Google Scholar · View at Scopus
  23. H. Wu, K. K. Bhopale, G. A. S. Ansari, and B. S. Kaphalia, “Ethanol-induced cytotoxicity in rat pancreatic acinar AR42J cells: role of fatty acid ethyl esters,” Alcohol and Alcoholism, vol. 43, no. 1, pp. 1–8, 2008. View at Publisher · View at Google Scholar · View at Scopus
  24. J. Werner, M. Saghir, A. L. Warshaw et al., “Alcoholic pancreatitis in rats: injury from nonoxidative metabolites of ethanol,” American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 283, no. 1, pp. G65–G73, 2002. View at Google Scholar · View at Scopus
  25. H. Wu, P. Cai, D. L. Clemens, T. R. Jerrells, G. A. Ansari, and B. S. Kaphalia, “Metabolic basis of ethanol-induced cytotoxicity in recombinant HepG2 cells: role of nonoxidative metabolism,” Toxicology and Applied Pharmacology, vol. 216, no. 2, pp. 238–247, 2006. View at Publisher · View at Google Scholar
  26. M. E. Beckemeier and P. S. Bora, “Fatty acid ethyl esters: potentially toxic products of myocardial ethanol metabolism,” Journal of Molecular and Cellular Cardiology, vol. 30, no. 11, pp. 2487–2494, 1998. View at Publisher · View at Google Scholar · View at Scopus
  27. K. K. Bhopale, H. Wu, P. J. Boor, V. L. Popov, G. A. S. Ansari, and B. S. Kaphalia, “Metabolic basis of ethanol-induced hepatic and pancreatic injury in hepatic alcohol dehydrogenase deficient deer mice,” Alcohol, vol. 39, no. 3, pp. 179–188, 2006. View at Publisher · View at Google Scholar · View at Scopus
  28. L. G. Lange and B. E. Sobel, “Mitochondrial dysfunction induced by fatty acid ethyl esters, myocardial metabolites of ethanol,” The Journal of Clinical Investigation, vol. 72, no. 2, pp. 724–731, 1983. View at Publisher · View at Google Scholar · View at Scopus
  29. J. Haorah, B. Knipe, S. Gorantla, J. Zheng, and Y. Persidsky, “Alcohol-induced blood-brain barrier dysfunction is mediated via inositol 1,4,5-triphosphate receptor (IP3R)-gated intracellular calcium release,” Journal of Neurochemistry, vol. 100, no. 2, pp. 324–336, 2007. View at Publisher · View at Google Scholar · View at Scopus
  30. S. Zakhari, “Alcohol metabolism and epigenetics changes,” Alcohol Research and Health, vol. 35, no. 1, pp. 6–16, 2013. View at Google Scholar · View at Scopus
  31. A. A. Nanji and S. Hiller-Sturmhöfel, “Apoptosis and necrosis: two types of cell death in alcoholic liver disease,” Alcohol Research and Health, vol. 21, no. 4, pp. 325–330, 1997. View at Google Scholar · View at Scopus
  32. H. Ishii, M. Adachi, J. C. Fernández-Checa, A. I. Cederbaum, I. V. Deaciuc, and A. A. Nanji, “Role of apoptosis in alcoholic liver injury,” Alcoholism: Clinical and Experimental Research, vol. 27, no. 7, pp. 1207–1212, 2003. View at Publisher · View at Google Scholar · View at Scopus
  33. A. S. Gukovskaya, O. A. Mareninova, I. V. Odinokova et al., “Cell death in pancreatitis: effects of alcohol,” Journal of Gastroenterology and Hepatology, vol. 21, supplemet 3, pp. S10–S13, 2006. View at Publisher · View at Google Scholar · View at Scopus
  34. Y. Wang, R. Hu, A. Lugea et al., “Ethanol feeding alters death signaling in the pancreas,” Pancreas, vol. 32, no. 4, pp. 351–359, 2006. View at Publisher · View at Google Scholar · View at Scopus
  35. S. Alfonso-Loeches, M. Pascual-Lucas, A. M. Blanco, I. Sanchez-Vera, and C. Guerri, “Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage,” Journal of Neuroscience, vol. 30, no. 24, pp. 8285–8295, 2010. View at Publisher · View at Google Scholar · View at Scopus
  36. S. Johansson, T. J. Ekström, Z. Marinova et al., “Dysregulation of cell death machinery in the prefrontal cortex of human alcoholics,” International Journal of Neuropsychopharmacology, vol. 12, no. 1, pp. 109–115, 2009. View at Publisher · View at Google Scholar · View at Scopus
  37. J. W. Olney, D. F. Wozniak, V. Jevtovic-Todorovic, N. B. Farber, P. Bittigau, and C. Ikonomidou, “Drug-induced apoptotic neurodegeneration in the developing brain,” Brain Pathology, vol. 12, no. 4, pp. 488–498, 2002. View at Google Scholar · View at Scopus
  38. J. Fernández-Solá, J. M. Nicolás, F. Fatjó et al., “Evidence of apoptosis in chronic alcoholic skeletal myopathy,” Human Pathology, vol. 34, no. 12, pp. 1247–1252, 2003. View at Publisher · View at Google Scholar
  39. A. Dey and A. I. Cederbaum, “Alcohol and oxidative liver injury,” Hepatology, vol. 43, supplement 1, pp. S63–S74, 2006. View at Publisher · View at Google Scholar · View at Scopus
  40. H. Rouach, V. Fataccioli, M. Gentil, S. W. French, M. Morimoto, and R. Nordmann, “Effect of chronic ethanol feeding on lipid peroxidation and protein oxidation in relation to liver pathology,” Hepatology, vol. 25, no. 2, pp. 351–355, 1997. View at Publisher · View at Google Scholar · View at Scopus
  41. J. Li, B. French, Y. Wu et al., “Liver hypoxia and lack of recovery after reperfusion at high blood alcohol levels in the intragastric feeding model of alcohol liver disease,” Experimental and Molecular Pathology, vol. 77, no. 3, pp. 184–192, 2004. View at Publisher · View at Google Scholar · View at Scopus
  42. S. W. French, “The role of hypoxia in the pathogenesis of alcoholic liver disease,” Hepatology Research, vol. 29, no. 2, pp. 69–74, 2004. View at Publisher · View at Google Scholar · View at Scopus
  43. S. K. Venugopal, J. Chen, Y. Zhang, D. Clemens, A. Follenzi, and M. A. Zern, “Role of MAPK phosphatase-1 in sustained activation of JNK during ethanol-induced apoptosis in hepatocyte-like VL-17A cells,” Journal of Biological Chemistry, vol. 282, no. 44, pp. 31900–31908, 2007. View at Publisher · View at Google Scholar · View at Scopus
  44. C. Ji and N. Kaplowitz, “Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice,” Gastroenterology, vol. 124, no. 5, pp. 1488–1499, 2003. View at Publisher · View at Google Scholar · View at Scopus
  45. T. M. Donohue Jr., D. L. McVicker, K. K. Kharbanda, M. L. Chaisson, and R. K. Zetterman, “Ethanol administration alters the proteolytic activity of hepatic lysosomes,” Alcoholism: Clinical and Experimental Research, vol. 18, no. 3, pp. 536–541, 1994. View at Publisher · View at Google Scholar · View at Scopus
  46. N. A. Osna and T. M. Donohue Jr., “Implication of altered proteasome function in alcoholic liver injury,” World Journal of Gastroenterology, vol. 13, no. 37, pp. 4931–4937, 2007. View at Google Scholar · View at Scopus
  47. F. Bardag-Gorce, F. W. van Leeuwen, V. Nguyen et al., “The role of the ubiquitin-proteasome pathway in the formation of Mallory bodies,” Experimental and Molecular Pathology, vol. 73, no. 2, pp. 75–83, 2002. View at Publisher · View at Google Scholar · View at Scopus
  48. S. Roychowdhury, M. R. Mcmullen, S. G. Pisano, X. Liu, and L. E. Nagy, “Absence of receptor interacting protein kinase 3 prevents ethanol-induced liver injury,” Hepatology, vol. 57, no. 5, pp. 1773–1783, 2013. View at Publisher · View at Google Scholar · View at Scopus
  49. A. Takamura, M. Komatsu, T. Hara et al., “Autophagy-deficient mice develop multiple liver tumors,” Genes and Development, vol. 25, no. 8, pp. 795–800, 2011. View at Publisher · View at Google Scholar · View at Scopus
  50. M. Komatsu, H. Kurokawa, S. Waguri et al., “The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1,” Nature Cell Biology, vol. 12, no. 3, pp. 213–223, 2010. View at Publisher · View at Google Scholar · View at Scopus
  51. R. Singh, S. Kaushik, Y. Wang et al., “Autophagy regulates lipid metabolism,” Nature, vol. 458, no. 7242, pp. 1131–1135, 2009. View at Publisher · View at Google Scholar · View at Scopus
  52. H. M. Ni, B. Woolbright, J. Williams et al., “Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy,” Journal of Hepatology, 2014. View at Publisher · View at Google Scholar
  53. J. A. Williams, S. Manley, and W. X. Ding, “New advances in molecular mechanisms and emerging therapeutic targets in alcoholic liver diseases,” World Journal of Gastroenterology, 2014. View at Google Scholar
  54. S. Mathews, M. Xu, H. Wang, A. Bertola, and B. Gao, “Animals models of gastrointestinal and liver diseases. Animal models of alcohol-induced liver disease: pathophysiology, translational relevance, and challenges,” The American Journal of Physiology-Gastrointestinal and Liver Physiology, vol. 306, no. 10, pp. G819–G823, 2014. View at Google Scholar
  55. D. Wu and A. I. Cederbaum, “Development and properties of HepG2 cells that constitutively express CYP2E1,” Methods in Molecular Biology, vol. 447, pp. 137–150, 2008. View at Publisher · View at Google Scholar · View at Scopus
  56. T. M. Donohue, N. A. Osna, and D. L. Clemens, “Recombinant Hep G2 cells that express alcohol dehydrogenase and cytochrome P450 2E1 as a model of ethanol-elicited cytotoxicity,” International Journal of Biochemistry and Cell Biology, vol. 38, no. 1, pp. 92–101, 2006. View at Publisher · View at Google Scholar · View at Scopus
  57. C. de Duve and R. Wattiaux, “Functions of lysosomes,” Annual Review of Physiology, vol. 28, pp. 435–492, 1966. View at Publisher · View at Google Scholar · View at Scopus
  58. M. Tsukada and Y. Ohsumi, “Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae,” FEBS Letters, vol. 333, no. 1-2, pp. 169–174, 1993. View at Publisher · View at Google Scholar · View at Scopus
  59. M. Thumm, R. Egner, B. Koch et al., “Isolation of autophagocytosis mutants of Saccharomyces cerevisiae,” The FEBS Letters, vol. 349, no. 2, pp. 275–280, 1994. View at Publisher · View at Google Scholar · View at Scopus
  60. N. Hosokawa, T. Hara, T. Kaizuka et al., “Nutrient-dependent mTORCl association with the ULK1-Atg13-FIP200 complex required for autophagy,” Molecular Biology of the Cell, vol. 20, no. 7, pp. 1981–1991, 2009. View at Publisher · View at Google Scholar · View at Scopus
  61. Y.-Y. Chang and T. P. Neufeld, “An Atg1/Atg13 complex with multiple roles in TOR-mediated autophagy regulation,” Molecular Biology of the Cell, vol. 20, no. 7, pp. 2004–2014, 2009. View at Publisher · View at Google Scholar · View at Scopus
  62. D. F. Egan, D. B. Shackelford, M. M. Mihaylova et al., “Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy,” Science, vol. 331, no. 6016, pp. 456–461, 2011. View at Publisher · View at Google Scholar · View at Scopus
  63. M. Hamasaki, N. Furuta, A. Matsuda et al., “Autophagosomes form at ER-mitochondria contact sites,” Nature, vol. 495, no. 7441, pp. 389–393, 2013. View at Publisher · View at Google Scholar · View at Scopus
  64. K. Matsunaga, E. Morita, T. Saitoh et al., “Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex via Atg14L,” The Journal of Cell Biology, vol. 190, no. 4, pp. 511–521, 2010. View at Publisher · View at Google Scholar · View at Scopus
  65. E. L. Axe, S. A. Walker, M. Manifava et al., “Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum,” Journal of Cell Biology, vol. 182, no. 4, pp. 685–701, 2008. View at Publisher · View at Google Scholar · View at Scopus
  66. T. Proikas-Cezanne, S. Waddell, A. Gaugel, T. Frickey, A. Lupas, and A. Nordheim, “WIPI-1α (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy,” Oncogene, vol. 23, no. 58, pp. 9314–9325, 2004. View at Publisher · View at Google Scholar · View at Scopus
  67. H. E. J. Polson, J. de Lartigue, D. J. Rigden et al., “Mammalian Atg18 (WIPI2) localizes to omegasome-anchored phagophores and positively regulates LC3 lipidation,” Autophagy, vol. 6, no. 4, pp. 506–522, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. G. Maria Fimia, A. Stoykova, A. Romagnoli et al., “Ambra1 regulates autophagy and development of the nervous system,” Nature, vol. 447, no. 7148, pp. 1121–1125, 2007. View at Publisher · View at Google Scholar · View at Scopus
  69. C. Liang, P. Feng, B. Ku et al., “Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG,” Nature Cell Biology, vol. 8, no. 7, pp. 688–698, 2006. View at Publisher · View at Google Scholar · View at Scopus
  70. Y. Takahashi, D. Coppola, N. Matsushita et al., “Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis,” Nature Cell Biology, vol. 9, no. 10, pp. 1142–1151, 2007. View at Publisher · View at Google Scholar · View at Scopus
  71. S. Pattingre, A. Tassa, X. Qu et al., “Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy,” Cell, vol. 122, no. 6, pp. 927–939, 2005. View at Publisher · View at Google Scholar · View at Scopus
  72. Y. Zhong, Q. J. Wang, X. Li et al., “Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex,” Nature Cell Biology, vol. 11, no. 4, pp. 468–476, 2009. View at Publisher · View at Google Scholar · View at Scopus
  73. Q. Sun, J. Zhang, W. Fan et al., “The RUN domain of Rubicon is important for hVps34 binding, lipid kinase inhibition, and autophagy suppression,” The Journal of Biological Chemistry, vol. 286, no. 1, pp. 185–191, 2011. View at Publisher · View at Google Scholar · View at Scopus
  74. Y. Ohsumi, “Molecular dissection of autophagy: Two ubiquitin-like systems,” Nature Reviews Molecular Cell Biology, vol. 2, no. 3, pp. 211–216, 2001. View at Publisher · View at Google Scholar · View at Scopus
  75. N. Mizushima, T. Noda, T. Yoshimori et al., “A protein conjugation system essential for autophagy,” Nature, vol. 395, no. 6700, pp. 395–398, 1998. View at Publisher · View at Google Scholar · View at Scopus
  76. Y. Ichimura, T. Kirisako, T. Takao et al., “A ubiquitin-like system mediates protein lipidation,” Nature, vol. 408, no. 6811, pp. 488–492, 2000. View at Publisher · View at Google Scholar · View at Scopus
  77. A. R. J. Young, E. Y. W. Chan, X. W. Hu et al., “Starvation and ULK1-dependent cycling of mammalian Atg9 between the TGN and endosomes,” Journal of Cell Science, vol. 119, no. 18, pp. 3888–3900, 2006. View at Publisher · View at Google Scholar · View at Scopus
  78. E. Itakura and N. Mizushima, “Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins,” Autophagy, vol. 6, no. 6, pp. 764–776, 2010. View at Publisher · View at Google Scholar · View at Scopus
  79. I. Vergne, E. Roberts, R. A. Elmaoued et al., “Control of autophagy initiation by phosphoinositide 3-phosphatase jumpy,” The EMBO Journal, vol. 28, no. 15, pp. 2244–2258, 2009. View at Publisher · View at Google Scholar · View at Scopus
  80. N. Taguchi-Atarashi, M. Hamasaki, K. Matsunaga et al., “Modulation of local Ptdins3P levels by the PI phosphatase MTMR3 regulates constitutive autophagy,” Traffic, vol. 11, no. 4, pp. 468–478, 2010. View at Publisher · View at Google Scholar · View at Scopus
  81. E. Itakura, C. Kishi-Itakura, and N. Mizushima, “The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes,” Cell, vol. 151, no. 6, pp. 1256–1269, 2012. View at Publisher · View at Google Scholar · View at Scopus
  82. K. K. Huynh, E. Eskelinen, C. C. Scott, A. Malevanets, P. Saftig, and S. Grinstein, “LAMP proteins are required for fusion of lysosomes with phagosomes,” EMBO Journal, vol. 26, no. 2, pp. 313–324, 2007. View at Publisher · View at Google Scholar · View at Scopus
  83. S. Jäger, C. Bucci, I. Tanida et al., “Role for Rab7 in maturation of late autophagic vacuoles,” Journal of Cell Science, vol. 117, no. 20, pp. 4837–4848, 2004. View at Publisher · View at Google Scholar · View at Scopus
  84. I. Tanida, Y. Sou, J. Ezaki, N. Minematsu-Ikeguchi, T. Ueno, and E. Kominami, “HsAtg4B/HsApg4B/autophagin-1 cleaves the carboxyl termini of three human Atg8 homologues and delipidates microtubule-associated protein light chain 3- and GABAA receptor-associated protein-phospholipid conjugates,” The Journal of Biological Chemistry, vol. 279, no. 35, pp. 36268–36276, 2004. View at Publisher · View at Google Scholar · View at Scopus
  85. N. Mizushima, Y. Ohsumi, and T. Yoshimori, “Autophagosome formation in mammalian cells,” Cell Structure and Function, vol. 27, no. 6, pp. 421–429, 2002. View at Publisher · View at Google Scholar · View at Scopus
  86. D. J. Klionsky, F. C. Abdalla, H. Abeliovich et al., “Guidelines for the use and interpretation of assays for monitoring autophagy,” Autophagy, vol. 8, pp. 445–544, 2012. View at Google Scholar
  87. H.-M. Ni, N. Boggess, M. R. Mcgill et al., “Liver-specific loss of Atg5 causes persistent activation of Nrf2 and protects against acetaminophen-induced liver injury,” Toxicological Sciences, vol. 127, no. 2, pp. 438–450, 2012. View at Publisher · View at Google Scholar · View at Scopus
  88. M. H. Sahani, E. Itakura, and N. Mizushima, “Expression of the autophagy substrate SQSTM1/p62 is restored during prolonged starvation depending on transcriptional upregulation and autophagy-derived amino acids,” Autophagy, vol. 10, no. 3, pp. 431–441, 2014. View at Publisher · View at Google Scholar
  89. H. M. Ni, K. Du, M. You, and W. X. Ding, “Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity,” American Journal of Pathology, vol. 183, pp. 1815–1825, 2013. View at Publisher · View at Google Scholar
  90. W. Ding, M. Li, X. Chen et al., “Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice,” Gastroenterology, vol. 139, no. 5, pp. 1740–1752, 2010. View at Publisher · View at Google Scholar · View at Scopus
  91. D. Wu, X. Wang, R. Zhou, L. Yang, and A. I. Cederbaum, “Alcohol steatosis and cytotoxicity: the role of cytochrome P4502E1 and autophagy,” Free Radical Biology and Medicine, vol. 53, no. 6, pp. 1346–1357, 2012. View at Publisher · View at Google Scholar · View at Scopus
  92. D. Wu, X. Wang, R. Zhou, and A. Cederbaum, “CYP2E1 enhances ethanol-induced lipid accumulation but impairs autophaghy in HepG2 E47 cells,” Biochemical and Biophysical Research Communications, vol. 402, no. 1, pp. 116–122, 2010. View at Publisher · View at Google Scholar · View at Scopus
  93. P. G. Thomes, R. A. Ehlers, C. S. Trambly et al., “Multilevel regulation of autophagosome content by ethanol oxidation in HepG2 cells,” Autophagy, vol. 9, no. 1, pp. 63–73, 2013. View at Publisher · View at Google Scholar · View at Scopus
  94. K. K. Kharbanda, D. L. McVicker, R. K. Zetterman, R. G. MacDonald, and T. M. Donohue Jr., “Flow cytometric analysis of vesicular pH in rat hepatocytes after ethanol administration,” Hepatology, vol. 26, no. 4, pp. 929–934, 1997. View at Publisher · View at Google Scholar · View at Scopus
  95. K. K. Kharbanda, D. L. McVicker, R. K. Zetterman, and T. M. Donohue Jr., “Ethanol consumption reduces the proteolytic capacity and protease activities of hepatic lysosomes,” Biochimica et Biophysica Acta, vol. 1245, no. 3, pp. 421–429, 1995. View at Google Scholar
  96. T. M. Donohue Jr., R. K. Zetterman, and D. J. Tuma, “Effect of chronic ethanol administration on protein catabolism in rat liver,” Alcoholism: Clinical and Experimental Research, vol. 13, no. 1, pp. 49–57, 1989. View at Publisher · View at Google Scholar · View at Scopus
  97. E. Baraona, M. A. Leo, S. A. Borowsky, and C. S. Lieber, “Alcoholic hematomegaly: accumulation of protein in the liver,” Science, vol. 190, no. 4216, pp. 794–795, 1975. View at Publisher · View at Google Scholar · View at Scopus
  98. T. M. Donohue Jr., “Autophagy and ethanol-induced liver injury,” World Journal of Gastroenterology, vol. 15, no. 10, pp. 1178–1185, 2009. View at Publisher · View at Google Scholar · View at Scopus
  99. C. W. Lin, H. Zhang, M. Li et al., “Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice,” Journal of Hepatology, vol. 58, no. 5, pp. 993–999, 2013. View at Publisher · View at Google Scholar · View at Scopus
  100. L. Yang, R. Rozenfeld, D. Wu, L. A. Devi, Z. Zhang, and A. Cederbaum, “Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy,” Free Radical Biology and Medicine, vol. 68, pp. 260–267, 2014. View at Publisher · View at Google Scholar
  101. Z. Yang and D. J. Klionsky, “Mammalian autophagy: core molecular machinery and signaling regulation,” Current Opinion in Cell Biology, vol. 22, no. 2, pp. 124–131, 2010. View at Publisher · View at Google Scholar · View at Scopus
  102. V. Facchinetti, W. Ouyang, H. Wei et al., “The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C,” The EMBO Journal, vol. 27, no. 14, pp. 1919–2030, 2008. View at Publisher · View at Google Scholar · View at Scopus
  103. T. Ikenoue, K. Inoki, Q. Yang, X. Zhou, and K. Guan, “Essential function of TORC2 in PKC and Akt turn motif phosphorylation, maturation and signalling,” The EMBO Journal, vol. 27, no. 14, pp. 1919–1931, 2008. View at Publisher · View at Google Scholar · View at Scopus
  104. J. E. Yeon, S. Califano, J. Xu, J. R. Wands, and S. M. de La Monte, “Potential role of PTEN phosphatase in ethanol-impaired survival signaling in the liver,” Hepatology, vol. 38, no. 3, pp. 703–714, 2003. View at Publisher · View at Google Scholar · View at Scopus
  105. J. He, S. de La Monte, and J. R. Wands, “Acute ethanol exposure inhibits insulin signaling in the liver,” Hepatology, vol. 46, no. 6, pp. 1791–1800, 2007. View at Publisher · View at Google Scholar · View at Scopus
  106. T. Porstmann, C. R. Santos, B. Griffiths et al., “SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth,” Cell Metabolism, vol. 8, no. 3, pp. 224–236, 2008. View at Publisher · View at Google Scholar · View at Scopus
  107. A. G. Jegga, L. Schneider, X. Ouyang, and J. Zhang, “Systems biology of the autophagy-lysosomal pathway,” Autophagy, vol. 7, no. 5, pp. 477–489, 2011. View at Publisher · View at Google Scholar · View at Scopus
  108. T. Zeng, C.-L. Zhang, F.-Y. Song et al., “PI3K/Akt pathway activation was involved in acute ethanol-induced fatty liver in mice,” Toxicology, vol. 296, no. 1–3, pp. 56–66, 2012. View at Publisher · View at Google Scholar · View at Scopus
  109. J. Kim, M. Kundu, B. Viollet, and K. Guan, “AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1,” Nature Cell Biology, vol. 13, no. 2, pp. 132–141, 2011. View at Publisher · View at Google Scholar · View at Scopus
  110. K. Inoki, T. Zhu, and K.-L. Guan, “TSC2 mediates cellular energy response to control cell growth and survival,” Cell, vol. 115, no. 5, pp. 577–590, 2003. View at Publisher · View at Google Scholar · View at Scopus
  111. D. M. Gwinn, D. B. Shackelford, D. F. Egan et al., “AMPK phosphorylation of raptor mediates a metabolic checkpoint,” Molecular Cell, vol. 30, no. 2, pp. 214–226, 2008. View at Publisher · View at Google Scholar · View at Scopus
  112. D. F. Egan, D. B. Shackelford, M. M. Mihaylova et al., “Phosphorylation of ULK1 (hATG1) by AMP—activated protein kinase connects energy sensing to mitophagy,” Science, vol. 331, no. 6016, pp. 456–461, 2011. View at Publisher · View at Google Scholar · View at Scopus
  113. J. Kim, Y. C. Kim, C. Fang et al., “Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy,” Cell, vol. 152, no. 1-2, pp. 290–303, 2013. View at Publisher · View at Google Scholar · View at Scopus
  114. H. R. Samari and P. O. Seglen, “Inhibition of hepatocytic autophagy by adenosine, aminoimidazole-4-carboxamide riboside, and N6-mercaptopurine riboside. Evidence for involvement of amp-activated protein kinase,” The Journal of Biological Chemistry, vol. 273, no. 37, pp. 23758–23763, 1998. View at Publisher · View at Google Scholar · View at Scopus
  115. L. Vucicevic, M. Misirkic, K. Janjetovic et al., “Compound C induces protective autophagy in cancer cells through AMPK inhibition-independent blockade of Akt/mTOR pathway,” Autophagy, vol. 7, no. 1, pp. 40–50, 2011. View at Publisher · View at Google Scholar · View at Scopus
  116. M. Hu, F. Wang, X. Li et al., “Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice,” Hepatology, vol. 55, no. 2, pp. 437–446, 2012. View at Publisher · View at Google Scholar · View at Scopus
  117. M. You, M. Matsumoto, C. M. Pacold, W. K. Cho, and D. W. Crabb, “The role of AMP-activated protein kinase in the action of ethanol in the liver,” Gastroenterology, vol. 127, no. 6, pp. 1798–1808, 2004. View at Publisher · View at Google Scholar · View at Scopus
  118. P. G. Thomes, C. S. Trambly, G. M. Thiele et al., “Proteasome activity and autophagosome content in liver are reciprocally regulated by ethanol treatment,” Biochemical and Biophysical Research Communications, vol. 417, no. 1, pp. 262–267, 2012. View at Publisher · View at Google Scholar · View at Scopus
  119. R. Scherz-Shouval, E. Shvets, E. Fass, H. Shorer, L. Gil, and Z. Elazar, “Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4,” The EMBO Journal, vol. 26, no. 7, pp. 1749–1760, 2007. View at Publisher · View at Google Scholar · View at Scopus
  120. D. Wu and A. I. Cederbaum, “Inhibition of autophagy promotes CYP2E1-dependent toxicity in HepG2 cells via elevated oxidative stress, mitochondria dysfunction and activation of p38 and JNK MAPK,” Redox Biology, vol. 1, no. 1, pp. 552–565, 2013. View at Publisher · View at Google Scholar
  121. H. Huang and D. J. Tindall, “Dynamic FoxO transcription factors,” Journal of Cell Science, vol. 120, no. 15, pp. 2479–2487, 2007. View at Publisher · View at Google Scholar · View at Scopus
  122. I. Tikhanovich, S. Kuravi, R. V. Campbell et al., “Regulation of FOXO3 by phosphorylation and methylation in hepatitis C virus infection and alcohol exposure,” Hepatology, vol. 59, no. 1, pp. 58–70, 2014. View at Publisher · View at Google Scholar
  123. H. Li, J. Liang, D. H. Castrillon, R. A. DePinho, E. N. Olson, and Z. Liu, “FoxO4 regulates tumor necrosis factor alpha-directed smooth muscle cell migration by activating matrix metalloproteinase 9 gene transcription,” Molecular and Cellular Biology, vol. 27, no. 7, pp. 2676–2686, 2007. View at Publisher · View at Google Scholar · View at Scopus
  124. L. Lin, J. D. Hron, and S. L. Peng, “Regulation of NF-κB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a,” Immunity, vol. 21, no. 2, pp. 203–213, 2004. View at Publisher · View at Google Scholar · View at Scopus
  125. A. Brunet, L. B. Sweeney, J. F. Sturgill et al., “Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase,” Science, vol. 303, no. 5666, pp. 2011–2015, 2004. View at Publisher · View at Google Scholar · View at Scopus
  126. Q. Xie, Y. Hao, L. Tao et al., “Lysine methylation of FOXO3 regulates oxidative stress-induced neuronal cell death,” EMBO Reports, vol. 13, no. 4, pp. 371–377, 2012. View at Publisher · View at Google Scholar · View at Scopus
  127. C. Mammucari, G. Milan, V. Romanello et al., “FoxO3 controls autophagy in skeletal muscle in vivo,” Cell Metabolism, vol. 6, no. 6, pp. 458–471, 2007. View at Publisher · View at Google Scholar · View at Scopus
  128. J. Zhao, J. J. Brault, A. Schild et al., “FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells,” Cell Metabolism, vol. 6, no. 6, pp. 472–483, 2007. View at Publisher · View at Google Scholar · View at Scopus
  129. K. E. van der Vos, P. Eliasson, T. Proikas-Cezanne et al., “Modulation of glutamine metabolism by the PI(3)K-PKB-FOXO network regulates autophagy,” Nature Cell Biology, vol. 14, no. 8, pp. 829–837, 2012. View at Publisher · View at Google Scholar · View at Scopus
  130. Y. Zhao, J. Yang, W. Liao et al., “Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity,” Nature Cell Biology, vol. 12, no. 7, pp. 665–675, 2010. View at Publisher · View at Google Scholar · View at Scopus
  131. T. Nakagawa and L. Guarente, “Sirtuins at a glance,” Journal of Cell Science, vol. 124, no. 6, pp. 833–838, 2011. View at Publisher · View at Google Scholar · View at Scopus
  132. M. C. Haigis and D. A. Sinclair, “Mammalian sirtuins: biological insights and disease relevance,” Annual Review of Pathology: Mechanisms of Disease, vol. 5, pp. 253–295, 2010. View at Publisher · View at Google Scholar · View at Scopus
  133. H. L. In, L. Cao, R. Mostoslavsky et al., “A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 9, pp. 3374–3379, 2008. View at Publisher · View at Google Scholar · View at Scopus
  134. S. Kume, T. Uzu, K. Horiike et al., “Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged kidney,” Journal of Clinical Investigation, vol. 120, no. 4, pp. 1043–1055, 2010. View at Publisher · View at Google Scholar · View at Scopus
  135. K. T. Howitz, K. J. Bitterman, H. Y. Cohen et al., “Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan,” Nature, vol. 425, no. 6954, pp. 191–196, 2003. View at Publisher · View at Google Scholar · View at Scopus
  136. S. Nepal and P. Park, “Activation of autophagy by globular adiponectin attenuates ethanol-induced apoptosis in HepG2 cells: involvement of AMPK/FoxO3A axis,” Biochimica et Biophysica Acta - Molecular Cell Research, vol. 1833, no. 10, pp. 2111–2125, 2013. View at Publisher · View at Google Scholar · View at Scopus
  137. S. Nepal, M. J. Kim, E. S. Lee et al., “Modulation of Atg5 expression by globular adiponectin contributes to autophagy flux and suppression of ethanol-induced cell death in liver cells,” Food and Chemical Toxicology, vol. 68, pp. 11–22, 2014. View at Publisher · View at Google Scholar
  138. P. Mandal, M. T. Pritchard, and L. E. Nagy, “Anti-inflammatory pathways and alcoholic liver disease: role of an adiponectin/interleukin-10/heme oxygenase-1 pathway,” World Journal of Gastroenterology, vol. 16, no. 11, pp. 1330–1336, 2010. View at Publisher · View at Google Scholar · View at Scopus
  139. E. L. Greer, P. R. Oskoui, M. R. Banko et al., “The energy sensor AMP-activated protein kinase directly regulates the mammalian FOXO3 transcription factor,” Journal of Biological Chemistry, vol. 282, no. 41, pp. 30107–30119, 2007. View at Publisher · View at Google Scholar · View at Scopus
  140. K. K. Kharbanda, “Alcoholic liver disease and methionine metabolism,” Seminars in Liver Disease, vol. 29, no. 2, pp. 155–165, 2009. View at Publisher · View at Google Scholar · View at Scopus
  141. K. K. Kharbanda, “Methionine metabolic pathway in alcoholic liver injury,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 16, no. 1, pp. 89–95, 2013. View at Publisher · View at Google Scholar · View at Scopus
  142. C. H. Halsted and V. Medici, “Aberrant hepatic methionine metabolism and gene methylation in the pathogenesis and treatment of alcoholic steatohepatitis,” International Journal of Hepatology, vol. 2012, Article ID 959746, 7 pages, 2012. View at Publisher · View at Google Scholar
  143. B. M. Sutter, X. Wu, S. Laxman, and B. P. Tu, “Methionine inhibits autophagy and promotes growth by inducing the SAM-responsive methylation of PP2A,” Cell, vol. 154, no. 2, pp. 403–415, 2013. View at Publisher · View at Google Scholar · View at Scopus
  144. A. Artal-Martinez de Narvajas, T. S. Gomez, J. S. Zhang et al., “Epigenetic regulation of autophagy by the methyltransferase G9a,” Molecular and Cellular Biology, vol. 33, pp. 3983–3993, 2013. View at Publisher · View at Google Scholar
  145. S. Li, P. Yang, E. Tian, and H. Zhang, “Arginine methylation modulates autophagic degradation of PGL granules in C. elegans,” Molecular Cell, vol. 52, pp. 421–433, 2013. View at Google Scholar
  146. W. X. Ding and X. M. Yin, “Mitophagy: mechanisms, pathophysiological roles, and analysis,” Biological Chemistry, vol. 393, no. 7, pp. 547–564, 2012. View at Publisher · View at Google Scholar · View at Scopus
  147. V. Kirkin, T. Lamark, T. Johansen, and I. Dikic, “NBR1 cooperates with p62 in selective autophagy of ubiquitinated targets,” Autophagy, vol. 5, no. 5, pp. 732–733, 2009. View at Publisher · View at Google Scholar · View at Scopus
  148. S. Manley, J. A. Williams, and W. X. Ding, “Role of p62/SQSTM1 in liver physiology and pathogenesis,” Experimental Biology and Medicine, vol. 238, no. 5, pp. 525–538, 2013. View at Publisher · View at Google Scholar · View at Scopus
  149. W.-X. Ding, H.-M. Ni, M. Li et al., “Nix is critical to two distinct phases of mitophagy, reactive oxygen species-mediated autophagy induction and Parkin-ubiquitin-p62-mediated mitochondrial priming,” The Journal of Biological Chemistry, vol. 285, no. 36, pp. 27879–27890, 2010. View at Publisher · View at Google Scholar · View at Scopus
  150. G. Matsumoto, K. Wada, M. Okuno, M. Kurosawa, and N. Nukina, “Serine 403 phosphorylation of p62/SQSTM1 regulates selective autophagic clearance of ubiquitinated proteins,” Molecular Cell, vol. 44, no. 2, pp. 279–289, 2011. View at Publisher · View at Google Scholar · View at Scopus
  151. Y. Ichimura, S. Waguri, Y. Sou et al., “Phosphorylation of p62 activates the Keap1-Nrf2 pathway during selective autophagy,” Molecular Cell, vol. 51, pp. 618–631, 2013. View at Publisher · View at Google Scholar · View at Scopus
  152. Y. Aoki, T. Kanki, Y. Hirota et al., “Phosphorylation of serine 114 on Atg32 mediates mitophagy,” Molecular Biology of the Cell, vol. 22, no. 17, pp. 3206–3217, 2011. View at Publisher · View at Google Scholar · View at Scopus
  153. P. Wild, H. Farhan, D. G. McEwan et al., “Phosphorylation of the autophagy receptor optineurin restricts Salmonella growth,” Science, vol. 333, no. 6039, pp. 228–233, 2011. View at Publisher · View at Google Scholar · View at Scopus
  154. H. Y. Gaisano and F. S. Gorelick, “New insights into the mechanisms of pancreatitis,” Gastroenterology, vol. 136, no. 7, pp. 2040–2044, 2009. View at Publisher · View at Google Scholar · View at Scopus
  155. A. S. Gukovskaya and I. Gukovsky, “Autophagy and pancreatitis,” American Journal of Physiology—Gastrointestinal and Liver Physiology, vol. 303, no. 9, pp. G993–G1003, 2012. View at Publisher · View at Google Scholar · View at Scopus
  156. I. Gukovsky, N. Li, J. Todoric, A. Gukovskaya, and M. Karin, “Inflammation, autophagy, and obesity: common features in the pathogenesis of pancreatitis and pancreatic cancer,” Gastroenterology, vol. 144, no. 6, pp. 1199.e4–1209.e4, 2013. View at Publisher · View at Google Scholar · View at Scopus
  157. J. M. Chen and C. Férec, “Chronic pancreatitis: genetics and pathogenesis,” Annual Review of Genomics and Human Genetics, vol. 10, pp. 63–87, 2009. View at Publisher · View at Google Scholar · View at Scopus
  158. R. Dawra, R. P. Sah, V. Dudeja et al., “Intra-acinar trypsinogen activation mediates early stages of pancreatic injury but not inflammation in mice with acute pancreatitis,” Gastroenterology, vol. 141, no. 6, pp. 2210.e2–2212.e2, 2011. View at Publisher · View at Google Scholar · View at Scopus
  159. S. Gaiser, J. Daniluk, Y. Liu et al., “Intracellular activation of trypsinogen in transgenic mice induces acute but not chronic pancreatitis,” Gut, vol. 60, no. 10, pp. 1379–1388, 2011. View at Publisher · View at Google Scholar · View at Scopus
  160. N. Li, X. Wu, R. G. Holzer et al., “Loss of acinar cell IKKα triggers spontaneous pancreatitis in mice,” Journal of Clinical Investigation, vol. 123, no. 5, pp. 2231–2243, 2013. View at Publisher · View at Google Scholar · View at Scopus
  161. B. Baumann, M. Wagner, T. Aleksic et al., “Constitutive IKK2 activation in acinar cells is sufficient to induce pancreatitis in vivo,” Journal of Clinical Investigation, vol. 117, no. 6, pp. 1502–1513, 2007. View at Publisher · View at Google Scholar · View at Scopus
  162. H. Algül, M. Treiber, M. Lesina et al., “Pancreas-specific RelA/p65 truncation increases susceptibility of acini to inflammation-associated cell death following cerulein pancreatitis,” The Journal of Clinical Investigation, vol. 117, no. 6, pp. 1490–1501, 2007. View at Publisher · View at Google Scholar · View at Scopus
  163. P. Neuhöfer, S. Liang, H. Einwächter et al., “Deletion of IκB activates RelA to reduce acute pancreatitis in mice through up-regulation of Spi2A,” Gastroenterology, vol. 144, no. 1, pp. 192–201, 2013. View at Publisher · View at Google Scholar · View at Scopus
  164. H. Huang, Y. Liu, J. Daniluk et al., “Activation of nuclear factor-κB in acinar cells increases the severity of pancreatitis in mice,” Gastroenterology, vol. 144, no. 1, pp. 202–210, 2013. View at Publisher · View at Google Scholar · View at Scopus
  165. D. A. Hess, S. E. Humphrey, J. Ishibashi et al., “Extensive pancreas regeneration following acinar-specific disruption of Xbp1 in mice,” Gastroenterology, vol. 141, no. 4, pp. 1463–1472, 2011. View at Publisher · View at Google Scholar · View at Scopus
  166. A. Lugea, D. Tischler, J. Nguyen et al., “Adaptive unfolded protein response attenuates alcohol-induced pancreatic damage,” Gastroenterology, vol. 140, no. 3, pp. 987–997, 2011. View at Publisher · View at Google Scholar · View at Scopus
  167. O. A. Mareninova, K. Sung, P. Hong et al., “Cell death in pancreatitis: caspases protect from necrotizing pancreatitis,” Journal of Biological Chemistry, vol. 281, no. 6, pp. 3370–3381, 2006. View at Publisher · View at Google Scholar · View at Scopus
  168. P. Vandenabeele, W. Declercq, F. van Herreweghe, and T. V. Berghe, “The role of the kinases RIP1 and RIP3 in TNF-induced necrosis,” Science Signaling, vol. 3, no. 115, article re4, 2010. View at Publisher · View at Google Scholar · View at Scopus
  169. S. He, L. Wang, L. Miao et al., “Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-α,” Cell, vol. 137, no. 6, pp. 1100–1111, 2009. View at Publisher · View at Google Scholar · View at Scopus
  170. L. Sun, H. Wang, Z. Wang et al., “Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase,” Cell, vol. 148, no. 1-2, pp. 213–227, 2012. View at Publisher · View at Google Scholar · View at Scopus
  171. Z. Wang, H. Jiang, S. Chen, F. Du, and X. Wang, “The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways,” Cell, vol. 148, no. 1-2, pp. 228–243, 2012. View at Publisher · View at Google Scholar · View at Scopus
  172. H. Wang, L. Sun, L. Su et al., “Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3,” Molecular Cell, vol. 54, no. 1, pp. 133–146, 2014. View at Google Scholar
  173. X. Chen, W. Li, J. Ren et al., “Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death,” Cell Research, vol. 24, no. 1, pp. 105–121, 2014. View at Publisher · View at Google Scholar
  174. Z. Cai, S. Jitkaew, J. Zhao et al., “Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis,” Nature Cell Biology, vol. 16, pp. 55–65, 2014. View at Publisher · View at Google Scholar
  175. M. C. Dufour and M. D. Adamson, “The epidemiology of alcohol-induced pancreatitis,” Pancreas, vol. 27, no. 4, pp. 286–290, 2003. View at Publisher · View at Google Scholar · View at Scopus
  176. D. Yadav and D. C. Whitcomb, “The role of alcohol and smoking in pancreatitis,” Nature Reviews Gastroenterology and Hepatology, vol. 7, no. 3, pp. 131–145, 2010. View at Publisher · View at Google Scholar · View at Scopus
  177. G. Talamini, C. Bassi, M. Falconi et al., “Alcohol and smoking as risk factors in chronic pancreatitis and pancreatic cancer,” Digestive Diseases and Sciences, vol. 44, no. 7, pp. 1303–1311, 1999. View at Publisher · View at Google Scholar · View at Scopus
  178. G. W. Olsen, J. S. Mandel, R. W. Gibson, L. W. Wattenberg, and L. M. Schuman, “A case-control study of pancreatic cancer and cigarettes, alcohol, coffee and diet,” The American Journal of Public Health, vol. 79, no. 8, pp. 1016–1019, 1989. View at Publisher · View at Google Scholar · View at Scopus
  179. P. Maisonneuve, A. B. Lowenfels, B. Müllhaupt et al., “Cigarette smoking accelerates progression of alcoholic chronic pancreatitis,” Gut, vol. 54, no. 4, pp. 510–514, 2005. View at Publisher · View at Google Scholar · View at Scopus
  180. M. R. Lankisch, M. Imoto, P. Layer, and E. P. DiMagno, “The effect of small amounts of alcohol on the clinical course of chronic pancreatitis,” Mayo Clinic Proceedings, vol. 76, no. 3, pp. 242–251, 2001. View at Publisher · View at Google Scholar · View at Scopus
  181. Y. Lin, A. Tamakoshi, T. Hayakawa, M. Ogawa, and Y. Ohno, “Associations of alcohol drinking and nutrient intake with chronic pancreatitis: Findings from a case-control study in Japan,” American Journal of Gastroenterology, vol. 96, no. 9, pp. 2622–2627, 2001. View at Publisher · View at Google Scholar · View at Scopus
  182. Y. C. Chan and P. S. Leung, “Acute pancreatitis: Animal models and recent advances in basic research,” Pancreas, vol. 34, no. 1, pp. 1–14, 2007. View at Publisher · View at Google Scholar · View at Scopus
  183. B. Lombardi, L. W. Estes, and D. S. Longnecker, “Acute hemorrhagic pancreatitis (massive necrosis) with fat necrosis induced in mice by DL ethionine fed with a choline deficient diet,” The American Journal of Pathology, vol. 79, no. 3, pp. 465–480, 1975. View at Google Scholar · View at Scopus
  184. S. Tani, H. Itoh, Y. Okabayashi et al., “New model of acute necrotizing pancreatitis induced by excessive doses of arginine in rats,” Digestive Diseases and Sciences, vol. 35, no. 3, pp. 367–374, 1990. View at Publisher · View at Google Scholar · View at Scopus
  185. K. H. Su, C. Cuthbertson, and C. Christophi, “Review of experimental animal models of acute pancreatitis,” HPB, vol. 8, no. 4, pp. 264–286, 2006. View at Publisher · View at Google Scholar · View at Scopus
  186. T. Takács, L. Czakó, É. Morschl et al., “The role of nitric oxide in edema formation in L-arginine-induced acute pancreatitis,” Pancreas, vol. 25, no. 3, pp. 277–282, 2002. View at Publisher · View at Google Scholar · View at Scopus
  187. L. Czako, T. Takacs, I. S. Varga et al., “Oxidative stress in distant organs and the effects of allopurinol during experimental acute pancreatitis,” International Journal of Pancreatology, vol. 27, no. 3, pp. 209–216, 2000. View at Publisher · View at Google Scholar · View at Scopus
  188. L. Czakó, T. Takács, I. S. Varga et al., “The pathogenesis of L-arginine-induced acute necrotizing pancreatitis: inflammatory mediators and endogenous cholecystokinin,” Journal of Physiology Paris, vol. 94, no. 1, pp. 43–50, 2000. View at Publisher · View at Google Scholar · View at Scopus
  189. Z. Rakonczay Jr., K. Jármay, J. Kaszaki et al., “NF-κB activation is detrimental in arginine-induced acute pancreatitis,” Free Radical Biology & Medicine, vol. 34, no. 6, pp. 696–709, 2003. View at Publisher · View at Google Scholar · View at Scopus
  190. T. Takács, Z. Rakonczay Jr., I. S. Varga et al., “Comparative effects of water immersion pretreatment on three different acute pancreatitis models in rats,” Biochemistry and Cell Biology, vol. 80, no. 2, pp. 241–251, 2002. View at Publisher · View at Google Scholar · View at Scopus
  191. A. Dabrowski, S. J. Konturek, J. W. Konturek, and A. Gabryelewicz, “Role of oxidative stress in the pathogenesis of caerulein-induced acute pancreatitis,” European Journal of Pharmacology, vol. 377, no. 1, pp. 1–11, 1999. View at Publisher · View at Google Scholar · View at Scopus
  192. O. A. Mareninova, K. Hermann, S. W. French et al., “Impaired autophagic flux mediates acinar cell vacuole formation and trypsinogen activation in rodent models of acute pancreatitis,” Journal of Clinical Investigation, vol. 119, no. 11, pp. 3340–3355, 2009. View at Publisher · View at Google Scholar · View at Scopus
  193. R. B. Pfeffer, O. Stasior, and J. W. Hinton, “The clinical picture of the sequential development of acute hemorrhagic pancreatitis in the dog,” Surgical Forum, vol. 8, pp. 248–251, 1957. View at Google Scholar
  194. G. Ohshio, A. Saluja, and M. L. Steer, “Effects of short-term pancreatic duct obstruction in rats,” Gastroenterology, vol. 100, no. 1, pp. 196–202, 1991. View at Google Scholar · View at Scopus
  195. M. M. Lerch, A. K. Saluja, M. Rünzi, R. Dawra, M. Saluja, and M. L. Steer, “Pancreatic duct obstruction triggers acute necrotizing pancreatitis in the opossum,” Gastroenterology, vol. 104, no. 3, pp. 853–861, 1993. View at Google Scholar · View at Scopus
  196. J. Schmidt, D. W. Rattner, K. Lewandrowski et al., “A better model of acute pancreatitis for evaluating therapy,” Annals of Surgery, vol. 215, no. 1, pp. 44–56, 1992. View at Publisher · View at Google Scholar · View at Scopus
  197. L. I. Cosen-Binker, M. G. Binker, C. C. Wang, W. Hong, and H. Y. Gaisano, “VAMP8 is the v-SNARE that mediates basolateral exocytosis in a mouse model of alcoholic pancreatitis,” The Journal of Clinical Investigation, vol. 118, no. 7, pp. 2535–2551, 2008. View at Publisher · View at Google Scholar · View at Scopus
  198. L. I. Cosen-Binker, P. P. L. Lam, M. G. Binker, and H. Y. Gaisano, “Alcohol-induced protein kinase Cα phosphorylation of Munc18c in carbachol-stimulated acini causes basolateral exocytosis,” Gastroenterology, vol. 132, no. 4, pp. 1527–1545, 2007. View at Publisher · View at Google Scholar · View at Scopus
  199. P. P. L. Lam, L. I. Cosen Binker, A. Lugea, S. J. Pandol, and H. Y. Gaisano, “Alcohol redirects CCK-mediated apical exocytosis to the acinar basolateral membrane in alcoholic pancreatitis,” Traffic, vol. 8, no. 5, pp. 605–617, 2007. View at Publisher · View at Google Scholar · View at Scopus
  200. N. Shalbueva, O. A. Mareninova, A. Gerloff et al., “Effects of oxidative alcohol metabolism on the mitochondrial permeability transition pore and necrosis in a mouse model of alcoholic pancreatitis,” Gastroenterology, vol. 144, no. 2, pp. 437.e6–446.e6, 2013. View at Publisher · View at Google Scholar · View at Scopus
  201. I. Gukovsky and A. S. Gukovskaya, “Impaired autophagy underlies key pathological responses of acute pancreatitis,” Autophagy, vol. 6, no. 3, pp. 428–429, 2010. View at Publisher · View at Google Scholar · View at Scopus
  202. F. Fortunato, H. Bürgers, F. Bergmann et al., “Impaired autolysosome formation correlates with Lamp-2 depletion: role of apoptosis, autophagy, and necrosis in pancreatitis,” Gastroenterology, vol. 137, no. 1, pp. 360.e1–360.e5, 2009. View at Publisher · View at Google Scholar · View at Scopus
  203. D. Grasso, A. Ropolo, A. Lo Ré et al., “Zymophagy, a novel selective autophagy pathway mediated by VMP1-USP9x-p62, prevents pancreatic cell death,” Journal of Biological Chemistry, vol. 286, no. 10, pp. 8308–8324, 2011. View at Publisher · View at Google Scholar · View at Scopus
  204. A. Ropolo, D. Grasso, R. Pardo et al., “The pancreatitis-induced vacuole membrane protein 1 triggers autophagy in mammalian cells,” Journal of Biological Chemistry, vol. 282, no. 51, pp. 37124–37133, 2007. View at Publisher · View at Google Scholar · View at Scopus
  205. D. Hashimoto, M. Ohmuraya, M. Hirota et al., “Involvement of autophagy in trypsinogen activation within the pancreatic acinar cells,” Journal of Cell Biology, vol. 181, no. 7, pp. 1065–1072, 2008. View at Publisher · View at Google Scholar · View at Scopus
  206. I. Gukovsky, S. J. Pandol, O. A. Mareninova, N. Shalbueva, W. Jia, and A. S. Gukovskaya, “Impaired autophagy and organellar dysfunction in pancreatitis,” Journal of Gastroenterology and Hepatology, vol. 27, no. 2, pp. 27–32, 2012. View at Publisher · View at Google Scholar · View at Scopus
  207. S. Lavandero, R. Troncoso, B. A. Rothermel, W. Martinet, J. Sadoshima, and J. A. Hill, “Cardiovascular autophagy: concepts, controversies, and perspectives,” Autophagy, vol. 9, pp. 1455–1466, 2013. View at Google Scholar
  208. A. Nakai, O. Yamaguchi, T. Takeda et al., “The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress,” Nature Medicine, vol. 13, no. 5, pp. 619–624, 2007. View at Publisher · View at Google Scholar · View at Scopus
  209. H. Zhu, P. Tannous, J. L. Johnstone et al., “Cardiac autophagy is a maladaptive response to hemodynamic stress,” The Journal of Clinical Investigation, vol. 117, no. 7, pp. 1782–1793, 2007. View at Publisher · View at Google Scholar · View at Scopus
  210. Y. Matsui, H. Takagi, X. Qu et al., “Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and beclin 1 in mediating autophagy,” Circulation Research, vol. 100, no. 6, pp. 914–922, 2007. View at Publisher · View at Google Scholar · View at Scopus
  211. S. Costanzo, A. di Castelnuovo, M. B. Donati, L. Iacoviello, and G. de Gaetano, “Alcohol consumption and mortality in patients with cardiovascular disease. A meta-analysis,” Journal of the American College of Cardiology, vol. 55, no. 13, pp. 1339–1347, 2010. View at Publisher · View at Google Scholar · View at Scopus
  212. C. D. Spies, M. Sander, K. Stangl et al., “Effects of alcohol on the heart,” Current Opinion in Critical Care, vol. 7, no. 5, pp. 337–343, 2001. View at Publisher · View at Google Scholar · View at Scopus
  213. W. Ge, R. Guo, and J. Ren, “AMP-dependent kinase and autophagic flux are involved in aldehyde dehydrogenase-2-induced protection against cardiac toxicity of ethanol,” Free Radical Biology and Medicine, vol. 51, no. 9, pp. 1736–1748, 2011. View at Publisher · View at Google Scholar · View at Scopus
  214. W. Ge and J. Ren, “MTOR-STAT3-notch signalling contributes to ALDH2-induced protection against cardiac contractile dysfunction and autophagy under alcoholism,” Journal of Cellular and Molecular Medicine, vol. 16, no. 3, pp. 616–626, 2012. View at Publisher · View at Google Scholar · View at Scopus
  215. R. Guo and J. Ren, “Deficiency in AMPK attenuates ethanol-induced cardiac contractile dysfunction through inhibition of autophagosome formation,” Cardiovascular Research, vol. 94, no. 3, pp. 480–491, 2012. View at Publisher · View at Google Scholar · View at Scopus
  216. R. Guo, N. Hu, M. R. Kandadi, and J. Ren, “Facilitated ethanol metabolism promotes cardiomyocyte contractile dysfunction through autophagy in murine hearts,” Autophagy, vol. 8, no. 4, pp. 593–608, 2012. View at Publisher · View at Google Scholar · View at Scopus
  217. M. R. Kandadi, N. Hu, and J. Ren, “ULK1 plays a critical role in AMPK-mediated myocardial autophagy and contractile dysfunction following acute alcohol challenge,” Current Pharmaceutical Design, vol. 19, no. 27, pp. 4874–4887, 2013. View at Publisher · View at Google Scholar · View at Scopus
  218. C. Harper and I. Matsumoto, “Ethanol and brain damage,” Current Opinion in Pharmacology, vol. 5, no. 1, pp. 73–78, 2005. View at Publisher · View at Google Scholar · View at Scopus
  219. N. Mizushima, A. Yamamoto, M. Matsui, T. Yoshimori, and Y. Ohsumi, “In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker,” Molecular Biology of the Cell, vol. 15, no. 3, pp. 1101–1111, 2004. View at Publisher · View at Google Scholar · View at Scopus
  220. T. Hara, K. Nakamura, M. Matsui et al., “Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice,” Nature, vol. 441, no. 7095, pp. 885–889, 2006. View at Publisher · View at Google Scholar · View at Scopus
  221. C. M. Smith, Y. Chen, M. L. Sullivan, P. M. Kochanek, and R. S. B. Clark, “Autophagy in acute brain injury: feast, famine, or folly?” Neurobiology of Disease, vol. 43, no. 1, pp. 52–59, 2011. View at Publisher · View at Google Scholar · View at Scopus
  222. G. Chen, Z. Ke, M. Xu et al., “Autophagy is a protective response to ethanol neurotoxicity,” Autophagy, vol. 8, no. 11, pp. 1577–1589, 2012. View at Publisher · View at Google Scholar · View at Scopus
  223. H. Wang, K. A. Bower, J. A. Frank, M. Xu, and J. Luo, “Hypoxic preconditioning alleviates ethanol neurotoxicity: the involvement of autophagy,” Neurotoxicity Research, vol. 24, no. 4, pp. 472–477, 2013. View at Publisher · View at Google Scholar · View at Scopus
  224. A. Alimov, H. Wang, M. Liu et al., “Expression of autophagy and UPR genes in the developing brain during ethanol-sensitive and resistant periods,” Metabolic Brain Disease, vol. 28, pp. 667–676, 2013. View at Publisher · View at Google Scholar · View at Scopus
  225. A. Pla, M. Pascual, J. Renau-Piqueras, and C. Guerri, “TLR4 mediates the impairment of ubiquitin-proteasome and autophagy-lysosome pathways induced by ethanol treatment in brain,” Cell Death and Disease, vol. 5, Article ID e1066, 2014. View at Publisher · View at Google Scholar
  226. M. Sandri, “Autophagy in skeletal muscle,” FEBS Letters, vol. 584, no. 7, pp. 1411–1416, 2010. View at Publisher · View at Google Scholar · View at Scopus
  227. B. A. Neel, Y. Lin, and J. E. Pessin, “Skeletal muscle autophagy: a new metabolic regulator,” Trends in Endocrinology & Metabolism, vol. 24, pp. 635–643, 2013. View at Google Scholar
  228. V. Tosch, H. M. Rohde, H. Tronchère et al., “A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy,” Human Molecular Genetics, vol. 15, no. 21, pp. 3098–3106, 2006. View at Publisher · View at Google Scholar · View at Scopus
  229. E. Masiero and M. Sandri, “Autophagy inhibition induces atrophy and myopathy in adult skeletal muscles,” Autophagy, vol. 6, no. 2, pp. 307–309, 2010. View at Publisher · View at Google Scholar · View at Scopus
  230. C. He, M. C. Bassik, V. Moresi et al., “Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis,” Nature, vol. 481, no. 7382, pp. 511–515, 2012. View at Publisher · View at Google Scholar · View at Scopus
  231. C. He, R. Sumpter Jr., and B. Levine, “Exercise induces autophagy in peripheral tissues and in the brain,” Autophagy, vol. 8, no. 10, pp. 1548–1551, 2012. View at Publisher · View at Google Scholar · View at Scopus
  232. K. H. Kim, Y. T. Jeong, H. Oh et al., “Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine,” Nature Medicine, vol. 19, no. 1, pp. 83–92, 2013. View at Publisher · View at Google Scholar · View at Scopus
  233. V. R. Preedy, D. C. Macallan, G. E. Griffin, E. B. Cook, T. N. Palmer, and T. J. Peters, “Total contractile protein contents and gene expression in skeletal muscle in response to chronic ethanol consumption in the rat,” Alcohol, vol. 14, no. 6, pp. 545–549, 1997. View at Publisher · View at Google Scholar · View at Scopus
  234. C. H. Lang, J. Fan, B. P. Lipton, B. J. Potter, and K. H. McDonough, “Modulation of the insulin-like growth factor system by chronic alcohol feeding,” Alcoholism: Clinical and Experimental Research, vol. 22, no. 4, pp. 823–829, 1998. View at Publisher · View at Google Scholar · View at Scopus
  235. S. Thapaliya, A. Runkana, M. R. McMullen et al., “Alcohol-induced autophagy contributes to loss in skeletal muscle mass,” Autophagy, vol. 10, no. 4, pp. 677–690, 2014. View at Google Scholar