MicroRNAs: Master Regulators of Ethanol Abuse and Toxicity?

Authors

  • Rajesh C. Miranda,

    1. From the Department of Neuroscience and Experimental Therapeutics (RCM, PS), College of Medicine, Texas A&M Health Science Ctr., College Station, Texas; Department of Animal Sciences, Rutgers (AZP), The State University of New Jersey, New Brunswick, New Jersey; Department of Gastroenterology (YT, AK), Rush University Medical Center, Chicago, Illinois; Waggoner Center for Alcohol & Addiction Research (DM), The University of Texas at Austin, Austin, Texas; Department of Surgery (Orthopaedic Division) (WS), Scott & White Hospital, Temple, Texas, Division of Metabolism and Health Effects (DH), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland.
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  • Andrzej Z. Pietrzykowski,

    1. From the Department of Neuroscience and Experimental Therapeutics (RCM, PS), College of Medicine, Texas A&M Health Science Ctr., College Station, Texas; Department of Animal Sciences, Rutgers (AZP), The State University of New Jersey, New Brunswick, New Jersey; Department of Gastroenterology (YT, AK), Rush University Medical Center, Chicago, Illinois; Waggoner Center for Alcohol & Addiction Research (DM), The University of Texas at Austin, Austin, Texas; Department of Surgery (Orthopaedic Division) (WS), Scott & White Hospital, Temple, Texas, Division of Metabolism and Health Effects (DH), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland.
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  • Yueming Tang,

    1. From the Department of Neuroscience and Experimental Therapeutics (RCM, PS), College of Medicine, Texas A&M Health Science Ctr., College Station, Texas; Department of Animal Sciences, Rutgers (AZP), The State University of New Jersey, New Brunswick, New Jersey; Department of Gastroenterology (YT, AK), Rush University Medical Center, Chicago, Illinois; Waggoner Center for Alcohol & Addiction Research (DM), The University of Texas at Austin, Austin, Texas; Department of Surgery (Orthopaedic Division) (WS), Scott & White Hospital, Temple, Texas, Division of Metabolism and Health Effects (DH), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland.
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  • Pratheesh Sathyan,

    1. From the Department of Neuroscience and Experimental Therapeutics (RCM, PS), College of Medicine, Texas A&M Health Science Ctr., College Station, Texas; Department of Animal Sciences, Rutgers (AZP), The State University of New Jersey, New Brunswick, New Jersey; Department of Gastroenterology (YT, AK), Rush University Medical Center, Chicago, Illinois; Waggoner Center for Alcohol & Addiction Research (DM), The University of Texas at Austin, Austin, Texas; Department of Surgery (Orthopaedic Division) (WS), Scott & White Hospital, Temple, Texas, Division of Metabolism and Health Effects (DH), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland.
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  • Dayne Mayfield,

    1. From the Department of Neuroscience and Experimental Therapeutics (RCM, PS), College of Medicine, Texas A&M Health Science Ctr., College Station, Texas; Department of Animal Sciences, Rutgers (AZP), The State University of New Jersey, New Brunswick, New Jersey; Department of Gastroenterology (YT, AK), Rush University Medical Center, Chicago, Illinois; Waggoner Center for Alcohol & Addiction Research (DM), The University of Texas at Austin, Austin, Texas; Department of Surgery (Orthopaedic Division) (WS), Scott & White Hospital, Temple, Texas, Division of Metabolism and Health Effects (DH), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland.
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  • Ali Keshavarzian,

    1. From the Department of Neuroscience and Experimental Therapeutics (RCM, PS), College of Medicine, Texas A&M Health Science Ctr., College Station, Texas; Department of Animal Sciences, Rutgers (AZP), The State University of New Jersey, New Brunswick, New Jersey; Department of Gastroenterology (YT, AK), Rush University Medical Center, Chicago, Illinois; Waggoner Center for Alcohol & Addiction Research (DM), The University of Texas at Austin, Austin, Texas; Department of Surgery (Orthopaedic Division) (WS), Scott & White Hospital, Temple, Texas, Division of Metabolism and Health Effects (DH), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland.
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  • Wayne Sampson,

    1. From the Department of Neuroscience and Experimental Therapeutics (RCM, PS), College of Medicine, Texas A&M Health Science Ctr., College Station, Texas; Department of Animal Sciences, Rutgers (AZP), The State University of New Jersey, New Brunswick, New Jersey; Department of Gastroenterology (YT, AK), Rush University Medical Center, Chicago, Illinois; Waggoner Center for Alcohol & Addiction Research (DM), The University of Texas at Austin, Austin, Texas; Department of Surgery (Orthopaedic Division) (WS), Scott & White Hospital, Temple, Texas, Division of Metabolism and Health Effects (DH), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland.
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  • Dale Hereld

    1. From the Department of Neuroscience and Experimental Therapeutics (RCM, PS), College of Medicine, Texas A&M Health Science Ctr., College Station, Texas; Department of Animal Sciences, Rutgers (AZP), The State University of New Jersey, New Brunswick, New Jersey; Department of Gastroenterology (YT, AK), Rush University Medical Center, Chicago, Illinois; Waggoner Center for Alcohol & Addiction Research (DM), The University of Texas at Austin, Austin, Texas; Department of Surgery (Orthopaedic Division) (WS), Scott & White Hospital, Temple, Texas, Division of Metabolism and Health Effects (DH), National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland.
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  • This critical review condenses the proceedings of a symposium held at the 32nd Annual Meeting of the Research Society on Alcoholism, June 20–24, San Diego, CA. miRNA annotation throughout this review is based on Human Genome Organization nomenclature (http://www.hugo-international.org/).

Reprint requests: Rajesh C. Miranda, Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Ctr., College Station, TX 77843-1114; Fax: 979-845-0790; E-mail: miranda@medicine.tamhsc.edu

Abstract

Ethanol exerts complex effects on human physiology and health. Ethanol is not only addictive, but it is also a fetal teratogen, an adult neurotoxin, and an etiologic agent in hepatic and cardiovascular disease, inflammation, bone loss, and fracture susceptibility. A large number of genes and signaling mechanisms have been implicated in ethanol’s deleterious effects leading to the suggestion that ethanol is a “dirty drug.” An important question is, are there cellular “master-switches” that can explain these pleiotropic effects of ethanol? MicroRNAs (miRNAs) have been recently identified as master regulators of the cellular transcriptome and proteome. miRNAs play an increasingly appreciated and crucial role in shaping the differentiation and function of tissues and organs in both health and disease. This critical review discusses new evidence showing that ethanol-sensitive miRNAs are indeed regulatory master-switches. More specifically, miRNAs control the development of tolerance, a crucial component of ethanol addiction. Other drugs of abuse also target some ethanol-sensitive miRNAs suggesting that common biochemical mechanisms underlie addiction. This review also discusses evidence that miRNAs mediate several ethanol pathologies, including disruption of neural stem cell proliferation and differentiation in the exposed fetus, gut leakiness that contributes to endotoxemia and alcoholic liver disease, and possibly also hepatocellular carcinomas and other gastrointestinal cancers. Finally, this review provides a perspective on emerging investigations into potential roles of miRNAs as mediators of ethanol’s effects on inflammation and fracture healing, as well as the potential for miRNAs as diagnostic biomarkers and as targets for therapeutic interventions for alcohol-related disorders.

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