title: Alcohol induced hepatic degeneration in a hepatitis C virus core protein transgenic mouse model.
abstract: Hepatitis C virus (HCV) has become a major public health issue. It is prevalent in most countries. HCV infection frequently begins without clinical symptoms, before progressing to persistent viremia, chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) in the majority of patients (70% to 80%). Alcohol is an independent cofactor that accelerates the development of HCC in chronic hepatitis C patients. The purpose of the current study was to evaluate ethanol-induced hepatic changes in HCV core-Tg mice and mutant core Tg mice. Wild type (NTG), core wild-Tg mice (TG-K), mutant core 116-Tg mice (TG-116) and mutant core 99-Tg mice (TG-99) were used in this investigation. All groups were given drinking water with 10% ethanol and 5% sucrose for 13 weeks. To observe liver morphological changes, we performed histopathological and immunohistochemical examinations. Histopathologically, NTG, TG-K and TG-116 mice showed moderate centrilobular necrosis, while severe centrilobular necrosis and hepatocyte dissociation were observed in TG-99 mice with increasing lymphocyte infiltration and piecemeal necrosis. In all groups, a small amount of collagen fiber was found, principally in portal areas. None of the mice were found to have myofibroblasts based on immunohistochemical staining specific for α-SMA. CYP2E1-positive cells were clearly detected in the centrilobular area in all groups. In the TG-99 mice, we also observed cells positive for CK8/18, TGF-β1 and phosphorylated (p)-Smad2/3 and p21 around the necrotic hepatocytes in the centrilobular area (p < 0.01). Based on our data, alcohol intake induced piecemeal necrosis and hepatocyte dissociation in the TG-99 mice. These phenomena involved activation of the TGF-β1/p-Smad2/3/p21 signaling pathway in hepatocytes. Data from this study will be useful for elucidating the association between alcohol intake and HCV infection.
authors.affiliation: College of Veterinary Medicine, Kyungpook National University, 80 Daehakro, Buk-gu, Daegu 702-701, Korea. ndh1122@hanmail.net.
authors.forename: Dong-Hyung
authors.initials: DH
authors.lastname: Noh
authors.affiliation: College of Veterinary Medicine, Kyungpook National University, 80 Daehakro, Buk-gu, Daegu 702-701, Korea. nikeun@hanmail.net.
authors.forename: Eun-Joo
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: College of Veterinary Medicine, Kyungpook National University, 80 Daehakro, Buk-gu, Daegu 702-701, Korea. pretersensual@hanmail.net.
authors.forename: Ah-Young
authors.initials: AY
authors.lastname: Kim
authors.affiliation: College of Veterinary Medicine, Kyungpook National University, 80 Daehakro, Buk-gu, Daegu 702-701, Korea. nikeun@hanmail.net.
authors.forename: Eun-Mi
authors.initials: EM
authors.lastname: Lee
authors.affiliation: College of Veterinary Medicine, Kyungpook National University, 80 Daehakro, Buk-gu, Daegu 702-701, Korea. mangelos@hanmail.net.
authors.forename: Chang-Woo
authors.initials: CW
authors.lastname: Min
authors.affiliation: College of Veterinary Medicine, Kyungpook National University, 80 Daehakro, Buk-gu, Daegu 702-701, Korea. qzpmqzpm@naver.com.
authors.forename: Kyung-Ku
authors.initials: KK
authors.lastname: Kang
authors.affiliation: College of Veterinary Medicine, Kyungpook National University, 80 Daehakro, Buk-gu, Daegu 702-701, Korea. 2myeongmi@naver.com.
authors.forename: Myeong-Mi
authors.initials: MM
authors.lastname: Lee
authors.affiliation: College of Veterinary Medicine, Kyungpook National University, 80 Daehakro, Buk-gu, Daegu 702-701, Korea. laversang@naver.com.
authors.forename: Sang-Hyeob
authors.initials: SH
authors.lastname: Kim
authors.affiliation: College of Veterinary Medicine, Kyungpook National University, 80 Daehakro, Buk-gu, Daegu 702-701, Korea. sse8679@naver.com.
authors.forename: Soo-Eun
authors.initials: SE
authors.lastname: Sung
authors.affiliation: College of Veterinary Medicine, Kyungpook National University, 80 Daehakro, Buk-gu, Daegu 702-701, Korea. meeyul@hanmail.net.
authors.forename: Meeyul
authors.initials: M
authors.lastname: Hwang
authors.affiliation: Korea Research Institute of Bioscience and Biotechnology, Daejon 305-333, Korea. dyyu10@kribb.re.kr.
authors.forename: Dae-Yeul
authors.initials: DY
authors.lastname: Yu
authors.affiliation: College of Veterinary Medicine, Kyungpook National University, 80 Daehakro, Buk-gu, Daegu 702-701, Korea. jeongks@knu.ac.kr.
authors.forename: Kyu-Shik
authors.initials: KS
authors.lastname: Jeong
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002492:Central Nervous System Depressants / Q000633:toxicity; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D053538:Keratin-18 / Q000378:metabolism; D053533:Keratin-8 / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000737:chemistry; D009154:Mutation; D009336:Necrosis / Q000139:chemically induced; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014758:Viral Core Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000199:Actins; C493957:Cdkn1a protein, mouse; D002492:Central Nervous System Depressants; D050759:Cyclin-Dependent Kinase Inhibitor p21; D053538:Keratin-18; D053533:Keratin-8; D051899:Smad2 Protein; D051900:Smad3 Protein; D053773:Transforming Growth Factor beta1; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1