title: Hepatocyte-specific deletion of ARNT (aryl hydrocarbon Receptor Nuclear Translocator) results in altered fibrotic gene expression in the thioacetamide model of liver injury.
abstract: OBJECTIVE
  Recent studies have shown that increased expression of liver hypoxia inducible factor 2-α (HIF-2α) leads to liver inflammation and a pro-fibrotic gene expression signature. Aryl hydrocarbon Receptor Nuclear Translocator (ARNT) is required for HIF-2α transcriptional activity and has previously been shown to regulate hepatic metabolism in mice. In these studies we examined the role of hepatocyte ARNT in the thioacetamide (TAA)-induced model of liver fibrosis.
  
  
  METHODS
  Hepatocyte-specific ARNT-null (LARNT) mice were created using an albumin promoter-driven Cre recombinase. LARNT and floxed control (FC) littermates were placed on chow diet and received twice weekly intraperitoneal injections of 0.15mg/g body weight of TAA for 13 weeks.
  
  
  RESULTS
  TAA treated LARNT and FC mice had a similar pattern of fibrosis. Quantification of Sirius red histology staining and hydroxyproline content revealed mixed results in terms of collagen deposition in LARNT livers. There was no significant difference in hepatocyte apoptosis or proliferation, as assessed by cleaved Caspase-3 and Ki67 respectively. LARNT mice had decreased macrophage accumulation, and decreased liver mRNA expression of Col1A1, Col1A2, Col5A1, Tgfβ1, Tgfβ2, Timp1 and Timp2.
  
  
  CONCLUSIONS
  Deletion of hepatocyte ARNT leads to altered expression of collagen associated mRNA and reduced macrophage infiltration in the TAA-induced model of liver fibrosis. It appears that hepatocyte ARNT is not a requirement for initiation of liver fibrogenesis, but does regulate pro-fibrotic gene expression and macrophage accumulation.
authors: Diabetes, Obesity & Endocrinology Group, Westmead Millennium Institute, Westmead Hospital, Sydney, NSW, Australia; Faculty of Medicine, University of Sydney, Westmead, Sydney, NSW, Australia; Diabetes and Transcription Factors Group, Garvan Institute of Medical Research, Sydney, NSW, Australia.
authors: Christopher
authors: C
authors: Scott
authors: Diabetes, Obesity & Endocrinology Group, Westmead Millennium Institute, Westmead Hospital, Sydney, NSW, Australia; Diabetes and Transcription Factors Group, Garvan Institute of Medical Research, Sydney, NSW, Australia.
authors: Kuan
authors: K
authors: Cha
authors: The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Sydney, NSW, Australia.
authors: Renuka
authors: R
authors: Rao
authors: The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Sydney, NSW, Australia.
authors: Christopher
authors: C
authors: Liddle
authors: Faculty of Medicine, University of Sydney, Westmead, Sydney, NSW, Australia; The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Sydney, NSW, Australia.
authors: Jacob
authors: J
authors: George
authors: Diabetes, Obesity & Endocrinology Group, Westmead Millennium Institute, Westmead Hospital, Sydney, NSW, Australia; Faculty of Medicine, University of Sydney, Westmead, Sydney, NSW, Australia; Diabetes and Transcription Factors Group, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent's Clinical School, University of NSW, Sydney, NSW, Australia; Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW Australia.
authors: Jenny E
authors: JE
authors: Gunton
mesh_terms: D000818:Animals; D017209:Apoptosis; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics*; D049109:Cell Proliferation; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D017353:Gene Deletion; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000209:etiology* / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D013853:Thioacetamide / Q000009:adverse effects
chemical_list: D016207:Cytokines; D012333:RNA, Messenger; D013853:Thioacetamide; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D003094:Collagen