Ethanol and tobacco smoke increase hepatic steatosis and hypoxia in the hypercholesterolemic apoE?/? mouse: Implications for a “multihit” hypothesis of fatty liver disease |
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| Authors: | Shannon M Bailey Sudheer K Mantena Telisha Millender-Swain Yavuz Cakir Nirag C Jhala David Chhieng Kent E Pinkerton Scott W Ballinger |
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| Institution: | 1. Department of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA;2. Center for Free Radical Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;3. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA;4. Institute of Toxicology and Environmental Health, University of California at Davis, Davis, CA 95616, USA;1. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA;2. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA;1. DISTAV, Dipartimento di Scienze della Terra, dell’Ambiente e della Vita, Università di Genova, Corso Europa 26, 16132, Genova, Italy;2. INBB, Istituto Nazionale Biostrutture e Biosistemi, Roma, Italy;3. Centro Alcologico Regionale Ligure- IRCCS AOU San Martino-IST, Genova, Italy;1. Lipid Research Laboratory, VA Medical Center, Department of Biochemistry and Molecular Medicine, The George Washington University Medical Center, Washington, D.C., USA;2. Laboratory of Hepatic Diseases, National Institute of Genomic Medicine - INMEGEN, CDMX, Mexico;3. National Council of Science and Technology - CONACYT, CDMX, Mexico;1. Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;2. Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;3. Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA;1. Department of Pharmacology, Federal University of Paraná, Curitiba, PR, Brazil;2. Department of Medical Pathology, Federal University of Paraná, Curitiba, PR, Brazil;3. Department of Veterinary Medicine, Federal University of Paraná, Curitiba, PR, Brazil;4. Department of Cell Biology, Federal University of Paraná, Curitiba, PR, Brazil;5. Tytgat Institute for Liver and Intestinal Research, University of Amsterdam, Amsterdam, The Netherlands |
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| Abstract: | Although epidemiologic studies indicate that combined exposure to cigarette smoke and alcohol increase the risk and severity of liver diseases, the molecular mechanisms responsible for hepatotoxicity are unknown. Similarly, emerging evidence indicates a linkage among hepatic steatosis and cardiovascular disease. Herein, we hypothesize that combined exposure to alcohol and environmental tobacco smoke (ETS) on a hypercholesterolemic background increases liver injury through oxidative/nitrative stress, hypoxia, and mitochondrial damage. To test this, male apoE?/? mice were exposed to an ethanol-containing diet, ETS alone, or a combination of the two, and histology and functional endpoints were compared to filtered-air-exposed, ethanol-naïve controls. Whereas ethanol consumption induced a mild steatosis, combined exposure to ethanol + ETS resulted in increased hepatic steatosis, inflammation, α-smooth muscle actin, and collagen. Exposure to ethanol + ETS induced the largest increase in CYP2E1 and iNOS protein, as well as increased 3-nitrotyrosine, mtDNA damage, and decreased cytochrome c oxidase protein, compared to all other groups. Similarly, the largest increase in HIF1α expression was observed in the ethanol + ETS group, indicating enhanced hypoxia. These studies demonstrate that ETS increases alcohol-dependent steatosis and hypoxic stress. Therefore, ETS may be a key environmental “hit” that accelerates and exacerbates alcoholic liver disease in hypercholesterolemic apoE?/? mice. |
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