title: Metabolic derivatives of alcohol and the molecular culprits of fibro-hepatocarcinogenesis: Allies or enemies?
abstract: Chronic intake of alcohol undoubtedly overwhelms the structural and functional capacity of the liver by initiating complex pathological events characterized by steatosis, steatohepatitis, hepatic fibrosis and cirrhosis. Subsequently, these initial pathological events are sustained and ushered into a more complex and progressive liver disease, increasing the risk of fibro-hepatocarcinogenesis. These coordinated pathological events mainly result from buildup of toxic metabolic derivatives of alcohol including but not limited to acetaldehyde (AA), malondialdehyde (MDA), CYP2E1-generated reactive oxygen species, alcohol-induced gut-derived lipopolysaccharide, AA/MDA protein and DNA adducts. The metabolic derivatives of alcohol together with other comorbidity factors, including hepatitis B and C viral infections, dysregulated iron metabolism, abuse of antibiotics, schistosomiasis, toxic drug metabolites, autoimmune disease and other non-specific factors, have been shown to underlie liver diseases. In view of the multiple etiology of liver diseases, attempts to delineate the mechanism by which each etiological factor causes liver disease has always proved cumbersome if not impossible. In the case of alcoholic liver disease (ALD), it is even more cumbersome and complicated as a result of the many toxic metabolic derivatives of alcohol with their varying liver-specific toxicities. In spite of all these hurdles, researchers and experts in hepatology have strived to expand knowledge and scientific discourse, particularly on ALD and its associated complications through the medium of scientific research, reviews and commentaries. Nonetheless, the molecular mechanisms underpinning ALD, particularly those underlying toxic effects of metabolic derivatives of alcohol on parenchymal and non-parenchymal hepatic cells leading to increased risk of alcohol-induced fibro-hepatocarcinogenesis, are still incompletely elucidated. In this review, we examined published scientific findings on how alcohol and its metabolic derivatives mount cellular attack on each hepatic cell and the underlying molecular mechanisms leading to disruption of core hepatic homeostatic functions which probably set the stage for the initiation and progression of ALD to fibro-hepatocarcinogenesis. We also brought to sharp focus, the complex and integrative role of transforming growth factor beta/small mothers against decapentaplegic/plasminogen activator inhibitor-1 and the mitogen activated protein kinase signaling nexus as well as their cross-signaling with toll-like receptor-mediated gut-dependent signaling pathways implicated in ALD and fibro-hepatocarcinogenesis. Looking into the future, it is hoped that these deliberations may stimulate new research directions on this topic and shape not only therapeutic approaches but also models for studying ALD and fibro-hepatocarcinogenesis.
authors.affiliation: Alex Boye, Yan Yang, Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei 230032, Anhui Province, China.
authors.forename: Alex
authors.initials: A
authors.lastname: Boye
authors.affiliation: Alex Boye, Yan Yang, Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei 230032, Anhui Province, China.
authors.forename: Yu-Hong
authors.initials: YH
authors.lastname: Zou
authors.affiliation: Alex Boye, Yan Yang, Department of Pharmacology and Institute of Natural Medicine, Anhui Medical University, Hefei 230032, Anhui Province, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yang
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000209:etiology* / Q000378:metabolism*; D000431:Ethanol / Q000378:metabolism* / Q000633:toxicity; D000069196:Gastrointestinal Microbiome; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008104:Liver Cirrhosis, Alcoholic / Q000209:etiology / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000150:complications* / Q000378:metabolism* / Q000473:pathology; D008113:Liver Neoplasms / Q000209:etiology* / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D017395:Plasminogen Activator Inhibitor 1; D016212:Transforming Growth Factor beta; D000431:Ethanol
keywords: Alcoholic hepatitis; Fibro-hepatocarcinogenesis; Lipopolysaccharide; Mitogen activated protein kinase; Small mother against decapentaplegic; Transforming growth factor beta