HCC development is associated to peripheral insulin resistance in a mouse model of NASH.
NAFLD is the most common liver disease worldwide but it is the potential evolution to NASH and eventually to hepatocellular carcinoma (HCC), even in the absence of cirrhosis, that makes NAFLD of such clinical importance.we aimed to create a mouse model reproducing the pathological spectrum of NAFLD...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4031080?pdf=render |
| _version_ | 1811259935020810240 |
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| author | Samuele De Minicis Laura Agostinelli Chiara Rychlicki Gian Pio Sorice Stefania Saccomanno Cinzia Candelaresi Andrea Giaccari Luciano Trozzi Irene Pierantonelli Eleonora Mingarelli Marco Marzioni Giovanna Muscogiuri Melania Gaggini Antonio Benedetti Amalia Gastaldelli Maria Guido Gianluca Svegliati-Baroni |
| author_facet | Samuele De Minicis Laura Agostinelli Chiara Rychlicki Gian Pio Sorice Stefania Saccomanno Cinzia Candelaresi Andrea Giaccari Luciano Trozzi Irene Pierantonelli Eleonora Mingarelli Marco Marzioni Giovanna Muscogiuri Melania Gaggini Antonio Benedetti Amalia Gastaldelli Maria Guido Gianluca Svegliati-Baroni |
| author_sort | Samuele De Minicis |
| collection | DOAJ |
| description | NAFLD is the most common liver disease worldwide but it is the potential evolution to NASH and eventually to hepatocellular carcinoma (HCC), even in the absence of cirrhosis, that makes NAFLD of such clinical importance.we aimed to create a mouse model reproducing the pathological spectrum of NAFLD and to investigate the role of possible co-factors in promoting HCC.mice were treated with a choline-deficient L-amino-acid-defined-diet (CDAA) or its control (CSAA diet) and subjected to a low-dose i.p. injection of CCl4 or vehicle. Insulin resistance was measured by the euglycemic-hyperinsulinemic clamp method. Steatosis, fibrosis and HCC were evaluated by histological and molecular analysis.CDAA-treated mice showed peripheral insulin resistance at 1 month. At 1-3 months, extensive steatosis and fibrosis were observed in CDAA and CDAA+CCl4 groups. At 6 months, equal increase in steatosis and fibrosis was observed between the two groups, together with the appearance of tumor. At 9 months of treatment, the 100% of CDAA+CCl4 treated mice revealed tumor versus 40% of CDAA mice. Insulin-like Growth Factor-2 (IGF-2) and Osteopontin (SPP-1) were increased in CDAA mice versus CSAA. Furthermore, Immunostaining for p-AKT, p-c-Myc and Glypican-3 revealed increased positivity in the tumors.the CDAA model promotes the development of HCC from NAFLD-NASH in the presence of insulin resistance but in the absence of cirrhosis. Since this condition is increasingly recognized in humans, our study provides a model that may help understanding mechanisms of carcinogenesis in NAFLD. |
| first_indexed | 2024-04-12T18:38:56Z |
| format | Article |
| id | doaj.art-cd2888c23b1e42fdb789e478ced6d534 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-12T18:38:56Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-cd2888c23b1e42fdb789e478ced6d5342022-12-22T03:20:51ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0195e9713610.1371/journal.pone.0097136HCC development is associated to peripheral insulin resistance in a mouse model of NASH.Samuele De MinicisLaura AgostinelliChiara RychlickiGian Pio SoriceStefania SaccomannoCinzia CandelaresiAndrea GiaccariLuciano TrozziIrene PierantonelliEleonora MingarelliMarco MarzioniGiovanna MuscogiuriMelania GagginiAntonio BenedettiAmalia GastaldelliMaria GuidoGianluca Svegliati-BaroniNAFLD is the most common liver disease worldwide but it is the potential evolution to NASH and eventually to hepatocellular carcinoma (HCC), even in the absence of cirrhosis, that makes NAFLD of such clinical importance.we aimed to create a mouse model reproducing the pathological spectrum of NAFLD and to investigate the role of possible co-factors in promoting HCC.mice were treated with a choline-deficient L-amino-acid-defined-diet (CDAA) or its control (CSAA diet) and subjected to a low-dose i.p. injection of CCl4 or vehicle. Insulin resistance was measured by the euglycemic-hyperinsulinemic clamp method. Steatosis, fibrosis and HCC were evaluated by histological and molecular analysis.CDAA-treated mice showed peripheral insulin resistance at 1 month. At 1-3 months, extensive steatosis and fibrosis were observed in CDAA and CDAA+CCl4 groups. At 6 months, equal increase in steatosis and fibrosis was observed between the two groups, together with the appearance of tumor. At 9 months of treatment, the 100% of CDAA+CCl4 treated mice revealed tumor versus 40% of CDAA mice. Insulin-like Growth Factor-2 (IGF-2) and Osteopontin (SPP-1) were increased in CDAA mice versus CSAA. Furthermore, Immunostaining for p-AKT, p-c-Myc and Glypican-3 revealed increased positivity in the tumors.the CDAA model promotes the development of HCC from NAFLD-NASH in the presence of insulin resistance but in the absence of cirrhosis. Since this condition is increasingly recognized in humans, our study provides a model that may help understanding mechanisms of carcinogenesis in NAFLD.http://europepmc.org/articles/PMC4031080?pdf=render |
| spellingShingle | Samuele De Minicis Laura Agostinelli Chiara Rychlicki Gian Pio Sorice Stefania Saccomanno Cinzia Candelaresi Andrea Giaccari Luciano Trozzi Irene Pierantonelli Eleonora Mingarelli Marco Marzioni Giovanna Muscogiuri Melania Gaggini Antonio Benedetti Amalia Gastaldelli Maria Guido Gianluca Svegliati-Baroni HCC development is associated to peripheral insulin resistance in a mouse model of NASH. PLoS ONE |
| title | HCC development is associated to peripheral insulin resistance in a mouse model of NASH. |
| title_full | HCC development is associated to peripheral insulin resistance in a mouse model of NASH. |
| title_fullStr | HCC development is associated to peripheral insulin resistance in a mouse model of NASH. |
| title_full_unstemmed | HCC development is associated to peripheral insulin resistance in a mouse model of NASH. |
| title_short | HCC development is associated to peripheral insulin resistance in a mouse model of NASH. |
| title_sort | hcc development is associated to peripheral insulin resistance in a mouse model of nash |
| url | http://europepmc.org/articles/PMC4031080?pdf=render |
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