Ethanol and tobacco smoke increase hepatic steatosis and hypoxia in the hypercholesterolemic apoE(-/-) mouse: implications for a "multihit" hypothesis of fatty liver disease.
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, alpha-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 HIF1alpha 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.
Bailey
Shannon M
SM
Department of Environmental Health Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA. sbailey@uab.edu
Mantena
Sudheer K
SK
Millender-Swain
Telisha
T
Cakir
Yavuz
Y
Jhala
Nirag C
NC
Chhieng
David
D
Pinkerton
Kent E
KE
Ballinger
Scott W
SW
D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects*; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D005786:Gene Expression Regulation; D006937:Hypercholesterolemia / Q000235:genetics; D000860:Hypoxia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*
D000199:Actins; D001057:Apolipoproteins E; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse