title: Analyses of hepatocellular proliferation in a mouse model of alpha-1-antitrypsin deficiency.
abstract: alpha-1-Antitrypsin (alpha1-AT) deficiency is the most common cause of metabolic pediatric liver disease. Hepatocellular injury is caused by toxicity of the mutant alpha-1-antitrypsin Z (alpha1-ATZ) molecule retained within hepatocytes. In these studies, we used the PiZ transgenic mouse model of alpha1-AT deficiency to examine hepatocellular proliferation in response to chronic liver injury resulting from this metabolic disease. The results showed increased hepatocellular proliferation and caspase 9 activation in male PiZ mice compared with female PiZ and wild-type mice. Hepatic alpha1-AT mRNA and protein expression also were increased in male PiZ mice, suggesting that greater hepatocellular proliferation and caspase activation in males results from increased hepatotoxicity associated with greater intracellular alpha1-ATZ accumulation. Testosterone treatment of female PiZ mice increased alpha1-ATZ expression and hepatocellular proliferation to a level comparable with that in males. In PiZ mice, hepatocytes devoid of intracellular alpha1-AT globules had a proliferative advantage compared with globule-containing hepatocytes. However, this advantage is relative because both globule-containing and globule-devoid hepatocytes exhibited comparable proliferation after partial hepatectomy. In conclusion, these data indicate that intracellular retention of mutant alpha1-ATZ is associated with a regenerative stimulus leading to increased hepatocellular proliferation, that gender-specific signals influence the degree of alpha1-AT expression and associated hepatic injury, and that hepatocytes devoid of alpha1-ATZ have a proliferative advantage over cells that accumulate the mutant protein. This selective proliferation suggests that hepatocellular transplantation may be applicable for treatment of this and other slowly progressive metabolic liver diseases.
authors.affiliation: Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA. rudnick_d@kids.wustl.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Rudnick
authors.forename: Yunjun
authors.initials: Y
authors.lastname: Liao
authors.forename: Jae-Koo
authors.initials: JK
authors.lastname: An
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Muglia
authors.forename: David H
authors.initials: DH
authors.lastname: Perlmutter
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Teckman
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology*; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D002455:Cell Division; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006498:Hepatectomy; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D013739:Testosterone / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000235:genetics* / Q000378:metabolism; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications*
chemical_list: D000728:Androgens; D016207:Cytokines; D000515:alpha 1-Antitrypsin; D013739:Testosterone; C506434:Casp9 protein, mouse; D053453:Caspase 9; D020169:Caspases