title: Growth hormone-dependent pathogenesis of human hepatic steatosis in a novel mouse model bearing a human hepatocyte-repopulated liver.
abstract: Clinical studies have shown a close association between nonalcoholic fatty liver disease and adult-onset GH deficiency, but the relevant molecular mechanisms are still unclear. No mouse model has been suitable to study the etiological relationship of human nonalcoholic fatty liver disease and human adult-onset GH deficiency under conditions similar to the human liver in vivo. We generated human (h-)hepatocyte chimeric mice with livers that were predominantly repopulated with h-hepatocytes in a h-GH-deficient state. The chimeric mouse liver was mostly repopulated with h-hepatocytes about 50 d after transplantation and spontaneously became fatty in the h-hepatocyte regions after about 70 d. Infusion of the chimeric mouse with h-GH drastically decreased steatosis, showing the direct cause of h-GH deficiency in the generation of hepatic steatosis. Using microarray profiles aided by real-time quantitative RT-PCR, comparison between h-hepatocytes from h-GH-untreated and -treated mice identified 14 GH-up-regulated and four GH-down-regulated genes, including IGF-I, SOCS2, NNMT, IGFLS, P4AH1, SLC16A1, SRD5A1, FADS1, and AKR1B10, respectively. These GH-up- and -down-regulated genes were expressed in the chimeric mouse liver at lower and higher levels than in human livers, respectively. Treatment of the chimeric mice with h-GH ameliorated their altered expression. h-Hepatocytes were separated from chimeric mouse livers for testing in vitro effects of h-GH or h-IGF-I on gene expression, and results showed that GH directly regulated the expression of IGF-I, SOCS2, NNMT, IGFALS, P4AH1, FADS1, and AKR1B10. In conclusion, the chimeric mouse is a novel h-GH-deficient animal model for studying in vivo h-GH-dependent human liver dysfunctions.
authors.affiliation: Yoshizato Project, Hiroshima Prefectural Institute of Industrial Science and Technology, Cooperative Link of Unique Science and Technology for Economy Revitalization, Higashihirosima, Hiroshima 739-0046, Japan.
authors.forename: Chise
authors.initials: C
authors.lastname: Tateno
authors.forename: Miho
authors.initials: M
authors.lastname: Kataoka
authors.forename: Rie
authors.initials: R
authors.lastname: Utoh
authors.forename: Asato
authors.initials: A
authors.lastname: Tachibana
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Itamoto
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Asahara
authors.forename: Fuyuki
authors.initials: F
authors.lastname: Miya
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yoshizato
mesh_terms: D000328:Adult; D000818:Animals; D000090943:Delta-5 Fatty Acid Desaturase; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology*; D005260:Female; D013006:Growth Hormone / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000637:transplantation*; D006801:Humans; D007150:Immunohistochemistry; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008099:Liver / Q000166:cytology* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000090943:Delta-5 Fatty Acid Desaturase; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; C000716847:FADS1 protein, human