title: Keratin mutation predisposes to mouse liver fibrosis and unmasks differential effects of the carbon tetrachloride and thioacetamide models.
abstract: OBJECTIVE
  Keratins 8 and 18 (K8/K18) are important hepatoprotective proteins. Animals expressing K8/K18 mutants show a marked susceptibility to acute/subacute liver injury. K8/K18 variants predispose to human end-stage liver disease and associate with fibrosis progression during chronic hepatitis C infection. We sought direct evidence for a keratin mutation-related predisposition to liver fibrosis using transgenic mouse models because the relationship between keratin mutations and cirrhosis is based primarily on human association studies.
  
  
  METHODS
  Mouse hepatofibrosis was induced by carbon tetrachloride (CCl(4)) or thioacetamide. Nontransgenic mice, or mice that over express either human Arg89-to-Cys (R89C mice) or wild-type K18 (WT mice) were used. The extent of fibrosis was evaluated by quantitative real-time reverse-transcription polymerase chain reaction of fibrosis-related genes, liver hydroxyproline measurement, and Picro-Sirius red staining and collagen immunofluorescence staining.
  
  
  RESULTS
  Compared with control animals, CCl(4) led to similar liver fibrosis but increased injury in K18 R89C mice. In contrast, thioacetamide caused more severe liver injury and fibrosis in K18 R89C as compared with WT and nontransgenic mice and resulted in increased messenger RNA levels of collagen, tissue inhibitor of metalloproteinase 1, matrix metalloproteinase 2, and matrix metalloproteinase 13. Analysis in nontransgenic mice showed that thioacetamide and CCl(4) have dramatically different molecular expression responses involving cytoskeletal and chaperone proteins.
  
  
  CONCLUSIONS
  Over expression of K18 R89C predisposes transgenic mice to thioacetamide- but not CCl(4)-induced liver fibrosis. Differences in the keratin mutation-associated fibrosis response among the 2 models raise the hypothesis that keratin variants may preferentially predispose to fibrosis in unique human liver diseases. Findings herein highlight distinct differences in the 2 widely used fibrosis models.
authors.affiliation: Department of Medicine, Palo Alto VA Medical Center, Palo Alto, California, USA.
authors.forename: Pavel
authors.initials: P
authors.lastname: Strnad
authors.forename: Guo-Zhong
authors.initials: GZ
authors.lastname: Tao
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhou
authors.forename: Masaru
authors.initials: M
authors.lastname: Harada
authors.forename: Diana M
authors.initials: DM
authors.lastname: Toivola
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Brunt
authors.forename: M Bishr
authors.initials: MB
authors.lastname: Omary
mesh_terms: D000818:Animals; D001148:Arsenamide / Q000633:toxicity; D002251:Carbon Tetrachloride / Q000633:toxicity; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D053538:Keratin-18 / Q000235:genetics* / Q000378:metabolism; D053533:Keratin-8 / Q000235:genetics* / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D012333:RNA, Messenger / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D053538:Keratin-18; D053533:Keratin-8; D012333:RNA, Messenger; D002251:Carbon Tetrachloride; D001148:Arsenamide