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.

Evaluation of the human relevance of the constitutive androstane receptor-mediated mode of action for rat hepatocellular tumor formation by the synthetic pyrethroid momfluorothrin

“…Recently, mice with human hepatocyte chimeric livers have been produced by transplanting human hepatocytes into albumin enhancer/promoter-driven urokinasetype plasminogen activator-transgenic severe combined immunodeficient (uPA/SCID) mice (Tateno et al, 2015a(Tateno et al, , 2015b(Tateno et al, , 2011(Tateno et al, , 2004(Tateno et al, , 2013. The host mouse hepatocytes are replaced with human hepatocytes in the livers of the chimeric mice.…”

“…Human hepatocytes in chimeric mice are considered to be deficient in growth hormone (GH) because the human GH receptor is unresponsive to mouse GH (Souza et al, 1995). Due to a lack of human GH in the chimeric mice, the chimeric mouse liver spontaneously becomes fatty in the human hepatocyte regions about 70 days after transplantation (Tateno et al, 2011). Therefore, to mimic the normal in vivo condition and to decrease steatosis, Alzet mini-pumps (Model 1002, Alzet Corporation, Palo Alto, CA, USA) containing recombinant human GH (Wako Pure Chemical Industries Ltd.), with a release rate of 8.2 μg/hr, were implanted in the subcutaneous tissue of mice under isoflurane anesthesia on the day prior to 7 days before the commencement of test chemical treatment.…”

Essential roles of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in the liver [Review]

“…In addition, hyaluronic acid levels, which are a fibrotic marker, showed a negative correlation with IGF-I and the IGF-I/IGFBP-3 ratio in patients with NAFLD [24]. Although GH obviously has an essential and direct role on heptocytes in the aspects of anti-steatotic action [33,38] and gene expression profiles [68], these results strongly suggest that IGF-I has GH-independent actions in the liver via various mechanisms (Fig. 1).…”

Oxidative Stress Attenuates Lipid Synthesis and Increases Mitochondrial Fatty Acid Oxidation in Hepatoma Cells Infected with Hepatitis C Virus

“…By contrast, these cytoplasmic vacuolations are absent from non-transplanted mice and regions dominated by murine constituents. These vacuolations have been characterized previously (91) and are due to hepatic steatosis (91). B, SCID/Alb-uPA mice (n ϭ 8) were transplanted with cryopreserved human hepatocytes at 10 -14 days after birth.…”

“…7A). This has been attributed to enhanced DNL arising from an inherent deficiency in this mouse model for human growth hormone (91). Although this is expected to limit interpretations regarding the impact of HCV infection on DNL, we considered using this model to examine hepatic ␤-oxidation during HCV infection because in the starved state, hepatic ␤-oxidation results in the production of ketone bodies, which in turn are used as an energy source, particularly by the brain (92).…”