title: Fat-Specific Protein 27/CIDEC Promotes Development of Alcoholic Steatohepatitis in Mice and Humans.
abstract: OBJECTIVE
  Alcoholic steatohepatitis (ASH) is the progressive form of alcoholic liver disease and may lead to cirrhosis and hepatocellular carcinoma. We studied mouse models and human tissues to identify molecules associated with ASH progression and focused on the mouse fat-specific protein 27 (FSP-27)/human cell death-inducing DFF45-like effector C (CIDEC) protein, which is expressed in white adipose tissues and promotes formation of fat droplets.
  
  
  METHODS
  C57BL/6N mice or mice with hepatocyte-specific disruption of Fsp27 (Fsp27(Hep-/-) mice) were fed the Lieber-Decarli ethanol liquid diet (5% ethanol) for 10 days to 12 weeks, followed by 1 or multiple binges of ethanol (5 or 6 g/kg) during the chronic feeding. Some mice were given an inhibitor (GW9662) of peroxisome proliferator-activated receptor γ (PPARG). Adenoviral vectors were used to express transgenes or small hairpin (sh) RNAs in cultured hepatocytes and in mice. Liver tissue samples were collected from ethanol-fed mice or from 31 patients with alcoholic hepatitis (AH) with biopsy-proved ASH and analyzed histologically and immunohistochemically and by transcriptome, immunoblotting, and real-time PCR analyses.
  
  
  RESULTS
  Chronic-plus-binge ethanol feeding of mice, which mimics the drinking pattern of patients with AH, produced severe ASH and mild fibrosis. Microarray analyses revealed similar alterations in expression of many hepatic genes in ethanol-fed mice and humans with ASH, including up-regulation of mouse Fsp27 (also called Cidec) and human CIDEC. Fsp27(Hep-/-) mice and mice given injections of adenovirus-Fsp27shRNA had markedly reduced ASH following chronic-plus-binge ethanol feeding. Inhibition of PPARG and cyclic AMP-responsive element binding protein H (CREBH) prevented the increases in Fsp27α and FSP27β mRNAs, respectively, and reduced liver injury in this chronic-plus-binge ethanol feeding model. Overexpression of FSP27 and ethanol exposure had synergistic effects in inducing production of mitochondrial reactive oxygen species and damage to hepatocytes in mice. Hepatic CIDEC mRNA expression was increased in patients with AH and correlated with the degree of hepatic steatosis and disease severity including mortality.
  
  
  CONCLUSIONS
  In mice, chronic-plus-binge ethanol feeding induces ASH that mimics some histological and molecular features observed in patients with AH. Hepatic expression of FSP27/CIDEC is highly up-regulated in mice following chronic-plus-binge ethanol feeding and in patients with AH; this up-regulation contributes to alcohol-induced liver damage.
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, Beijing, China.
authors.forename: Ming-Jiang
authors.initials: MJ
authors.lastname: Xu
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Liver Unit-Internal Medicine Department, Vall d'Hebron Hospital, Vall d'Hebron Institut de Recerca, Barcelona, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Altamirano
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Binxia
authors.initials: B
authors.lastname: Chang
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Adeline
authors.initials: A
authors.lastname: Bertola
authors.affiliation: Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Gemma
authors.initials: G
authors.lastname: Odena
authors.affiliation: GoPath Diagnostics, LLC, Chicago, Illinois.
authors.forename: Jim
authors.initials: J
authors.lastname: Lu
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: Faculty of Pharmaceutical Science, Fukuoka University, Fukuoka, Japan.
authors.forename: Kimihiko
authors.initials: K
authors.lastname: Matsusue
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Matsubara
authors.affiliation: Section of Oxidative Stress and Tissue Injury, Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Shioko
authors.initials: S
authors.lastname: Kimura
authors.affiliation: Section of Oxidative Stress and Tissue Injury, Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Pal
authors.initials: P
authors.lastname: Pacher
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Liver Unit-Internal Medicine Department, Vall d'Hebron Hospital, Vall d'Hebron Institut de Recerca, Barcelona, Spain; Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Ramon
authors.initials: R
authors.lastname: Bataller
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland. Electronic address: bgao@mail.nih.gov.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
mesh_terms: D000328:Adult; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D063425:Binge Drinking; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005235:Fatty Liver, Alcoholic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; C472088:CIDEC protein, human; C500051:Creb3l3 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D047495:PPAR gamma; D011506:Proteins; D017382:Reactive Oxygen Species; C525805:fat-specific protein 27, mouse
keywords: Endoplasmic Reticulum; Inflammation; Lipid Metabolism; Translational Research