The autophagic response to alcohol toxicity: The missing layer
Authors: Nabil Eid, Yuko Ito, Yoshinori Otsuki
Journal: Journal of Hepatology (2013)

Alcohol and toxicityJournal of HepatologyVol. 59Issue 2PreviewExcessive alcohol intake is a major public health challenge worldwide and has been identified as one of the main determinants of a variety of non-communicable diseases [1]. The World Health Organization (WHO) estimates that 4.5% of the global burden of disease and injury, and 4% of all deaths worldwide are attributable to alcohol [2]. Alcohol is the leading risk factor for death among males aged 15–59 years, particularly in Eastern Europe [2,3]. Full-Text PDF Open AccessReply to: "The autophagic response to alcohol toxicity: The missing layer"Journal of HepatologyVol. 59Issue 2PreviewWe appreciate the interest of Eid et al. [1] in the Hepatology Snapshot on "Alcohol and toxicity" [2]. The authors posit that autophagy, a physiological mechanism that is ubiquitous and critical for maintaining balance in synthesis, degradation, and recycling of proteins, lipids and other macromolecules, represents the central mechanism that connects key toxicity mediators and molecular mechanisms with alcohol-induced disturbances in target tissues. Full-Text PDF Open Access We read with interest the manuscript by Rusyn and Bataller [[1]Rusyn I, Bataller R. Alcohol and toxicity. J Hepatol 2013;59:387–388.Google Scholar]. The authors summarized the various mechanisms of alcohol-induced toxicity and organ damage in a seven-layered diagram. In this diagram, the authors demonstrated that alcohol toxic mediators, as acetaldehyde and ROS, activate several cellular molecular mechanisms such as hypoxia, ER stress, and DNA damage (layer 4), resulting in pathological changes in most body organs (layer 5). These changes include steatosis, apoptosis/necrosis, fibrosis, and cancer. However, we do believe that there is a missing link between layer 4 and 5; that is autophagy which is an essential regulator of alcohol toxicity, therefore, we suggest this missing layer to be autophagy layer (4R) (Fig. 1). Autophagy is a lysosomal degradation of cellular components within autophagic vacuoles following multiple forms of cellular stress, including starvation, hypoxia, oxidative stress, damaged DNA, protein aggregates, damaged mitochondria, and lipogenic challenge. Whether it is bulk or selective autophagy (mitophagy, lipophagy), recent studies conclude that ethanol-induced autophagy may regulate steatosis, apoptosis, fibrosis and even cancer in various organs [2Ding W.X. Li M. Chen X. Ni H.M. Lin C.W. Gao W. et al.Autophagy reduces acute ethanol induced hepatotoxicity and steatosis in mice.Gastroenterol. 2010; 139: 1740-1752Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar, 3Eid N. Ito Y. Maemura K. Otsuki Y. Elevated autophagic sequestration of mitochondria and lipid droplets in steatotic hepatocytes of chronic ethanol-treated rats: an immunohistochemical and electron microscopic study.J Mol Histol. 2013; ([Epub ahead of print])https://doi.org/10.1007/s10735-013-9483-xCrossref PubMed Scopus (89) Google Scholar, 4Eid N. Ito Y. Otsuki Y. Enhanced mitophagy in Sertoli cells of ethanol-treated rats: morphological evidence and clinical relevance.J Mol Histol. 2012; 43: 71-80Crossref PubMed Scopus (32) Google Scholar, 5Eid N.A. Shibata M.A. Ito Y. Kusakabe K. Hammad H. Otsuki Y. Involvement of Fas system and active caspases in apoptotic signalling in testicular germ cells of ethanol-treated rats.Int J Androl. 2002; 25: 159-167Crossref PubMed Scopus (54) Google Scholar, 6Sanchez-Alvarez R. Martinez-Outschoorn U.E. Lin Z. Lamb R. Hulit J. Howell A. et al.Ethanol exposure induces the cancer-associated fibroblast phenotype and lethal tumor metabolism: implications for breast cancer prevention.Cell Cycle. 2013; 12: 289-301Crossref PubMed Scopus (39) Google Scholar]. In a recent study [[3]Eid N. Ito Y. Maemura K. Otsuki Y. Elevated autophagic sequestration of mitochondria and lipid droplets in steatotic hepatocytes of chronic ethanol-treated rats: an immunohistochemical and electron microscopic study.J Mol Histol. 2013; ([Epub ahead of print])https://doi.org/10.1007/s10735-013-9483-xCrossref PubMed Scopus (89) Google Scholar], we have observed enhanced autophagic sequestration of mitochondria and lipid droplets in steatotic hepatocytes of chronic ethanol-treated rats, which may reflect ethanol toxicity. This could represent a selective survival mechanism through the autophagic clearance of pro-apoptotic damaged mitochondria (mitophagy) and excessive fat (lipophagy), ameliorating the progression of alcohol liver disease [[2]Ding W.X. Li M. Chen X. Ni H.M. Lin C.W. Gao W. et al.Autophagy reduces acute ethanol induced hepatotoxicity and steatosis in mice.Gastroenterol. 2010; 139: 1740-1752Abstract Full Text Full Text PDF PubMed Scopus (406) Google Scholar]. Moreover, while germ cells underwent marked apoptotic cell death in the testis of ethanol-treated rats, mitophagy was activated in Sertoli cells, as anti-apoptotic mechanism essential for spermatogenesis [4Eid N. Ito Y. Otsuki Y. Enhanced mitophagy in Sertoli cells of ethanol-treated rats: morphological evidence and clinical relevance.J Mol Histol. 2012; 43: 71-80Crossref PubMed Scopus (32) Google Scholar, 5Eid N.A. Shibata M.A. Ito Y. Kusakabe K. Hammad H. Otsuki Y. Involvement of Fas system and active caspases in apoptotic signalling in testicular germ cells of ethanol-treated rats.Int J Androl. 2002; 25: 159-167Crossref PubMed Scopus (54) Google Scholar]. Ethanol-induced oxidative stress in stromal fibroblasts of breast cancer activates autophagy/mitophagy in these cells, driving the induction of ketone body production in the tumor stroma and subsequently fueling the metabolism of epithelial cancer cells and cancer progression [[6]Sanchez-Alvarez R. Martinez-Outschoorn U.E. Lin Z. Lamb R. Hulit J. Howell A. et al.Ethanol exposure induces the cancer-associated fibroblast phenotype and lethal tumor metabolism: implications for breast cancer prevention.Cell Cycle. 2013; 12: 289-301Crossref PubMed Scopus (39) Google Scholar]. Alcohol was reported to activate hepatic stellate cells [[7]Reeves H.L. Burt A.D. Wood S. Day C.P. Hepatic stellate cell activation occurs in the absence of hepatitis in alcoholic liver disease and correlates with the severity of steatosis.J Hepatol. 1996; 25: 677-683Abstract Full Text PDF PubMed Scopus (134) Google Scholar] and there is a possibility of ethanol-induced activation of autophagy in these cells and subsequent stimulation of fibrogenesis [[8]Thoen L.F. Guimarães E.L. Grunsven L.A. Autophagy: a new player in hepatic stellate cell activation.Autophagy. 2012; 8: 126-128Crossref PubMed Scopus (56) Google Scholar]. Finally, we would like to congratulate Rusyn and Bataller [[1]Rusyn I, Bataller R. Alcohol and toxicity. J Hepatol 2013;59:387–388.Google Scholar] for their work which summarizes the various mechanisms of alcohol toxicity and the resulting pathology in most body systems and we hope that our comments will add to this work. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.