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...
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| Veröffentlicht in: | PloS one 2014-05, Vol.9 (5), p.e97136 |
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| creator | De Minicis, Samuele Agostinelli, Laura Rychlicki, Chiara Sorice, Gian Pio Saccomanno, Stefania Candelaresi, Cinzia Giaccari, Andrea Trozzi, Luciano Pierantonelli, Irene Mingarelli, Eleonora Marzioni, Marco Muscogiuri, Giovanna Gaggini, Melania Benedetti, Antonio Gastaldelli, Amalia Guido, Maria Svegliati-Baroni, Gianluca |
| 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. |
| doi_str_mv | 10.1371/journal.pone.0097136 |
| format | Article |
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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.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0097136</identifier><identifier>PMID: 24853141</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Age Factors ; AKT protein ; Amino acids ; Analysis ; Animals ; Biocompatibility ; Biology and Life Sciences ; Biomedical materials ; c-Myc protein ; Carbon tetrachloride ; Carcinogenesis ; Carcinogens ; Carcinoma, Hepatocellular - etiology ; Choline ; Choline Deficiency ; Cirrhosis ; Diabetes ; Diet ; Disease Models, Animal ; Endocrinology ; Fibrosis ; Food, Formulated ; Gastroenterology ; Growth factors ; Heparan sulfate proteoglycans ; Hepatocellular carcinoma ; Hepatology ; Inflammation ; Insulin ; Insulin resistance ; Insulin Resistance - physiology ; Insulin-Like Growth Factor II - metabolism ; Insulin-like growth factors ; Liver ; Liver cancer ; Liver cirrhosis ; Liver diseases ; Liver Neoplasms - etiology ; Medicine and Health Sciences ; Metabolic disorders ; Metabolic syndrome ; Mice ; Non-alcoholic Fatty Liver Disease - complications ; Non-alcoholic Fatty Liver Disease - physiopathology ; Nutrient deficiency ; Obesity ; Osteopontin ; Osteopontin - metabolism ; Pathogenesis ; Physiology ; Proto-Oncogene Proteins c-myc - metabolism ; Research and Analysis Methods ; Rodents ; Steatosis ; Tumors</subject><ispartof>PloS one, 2014-05, Vol.9 (5), p.e97136</ispartof><rights>COPYRIGHT 2014 Public Library of Science</rights><rights>2014 De Minicis et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2014 De Minicis et al 2014 De Minicis et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c758t-7241c345447c2d7adab9b9dbf7ebec3d239685e554a590195158b9ab9a8bdbea3</citedby><cites>FETCH-LOGICAL-c758t-7241c345447c2d7adab9b9dbf7ebec3d239685e554a590195158b9ab9a8bdbea3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031080/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031080/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,724,777,781,861,882,2096,2915,23847,27905,27906,53772,53774,79349,79350</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24853141$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Bartosch, Birke</contributor><creatorcontrib>De Minicis, Samuele</creatorcontrib><creatorcontrib>Agostinelli, Laura</creatorcontrib><creatorcontrib>Rychlicki, Chiara</creatorcontrib><creatorcontrib>Sorice, Gian Pio</creatorcontrib><creatorcontrib>Saccomanno, Stefania</creatorcontrib><creatorcontrib>Candelaresi, Cinzia</creatorcontrib><creatorcontrib>Giaccari, Andrea</creatorcontrib><creatorcontrib>Trozzi, Luciano</creatorcontrib><creatorcontrib>Pierantonelli, Irene</creatorcontrib><creatorcontrib>Mingarelli, Eleonora</creatorcontrib><creatorcontrib>Marzioni, Marco</creatorcontrib><creatorcontrib>Muscogiuri, Giovanna</creatorcontrib><creatorcontrib>Gaggini, Melania</creatorcontrib><creatorcontrib>Benedetti, Antonio</creatorcontrib><creatorcontrib>Gastaldelli, Amalia</creatorcontrib><creatorcontrib>Guido, Maria</creatorcontrib><creatorcontrib>Svegliati-Baroni, Gianluca</creatorcontrib><title>HCC development is associated to peripheral insulin resistance in a mouse model of NASH</title><title>PloS one</title><addtitle>PLoS One</addtitle><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.</description><subject>Age Factors</subject><subject>AKT protein</subject><subject>Amino acids</subject><subject>Analysis</subject><subject>Animals</subject><subject>Biocompatibility</subject><subject>Biology and Life Sciences</subject><subject>Biomedical materials</subject><subject>c-Myc protein</subject><subject>Carbon tetrachloride</subject><subject>Carcinogenesis</subject><subject>Carcinogens</subject><subject>Carcinoma, Hepatocellular - etiology</subject><subject>Choline</subject><subject>Choline Deficiency</subject><subject>Cirrhosis</subject><subject>Diabetes</subject><subject>Diet</subject><subject>Disease Models, Animal</subject><subject>Endocrinology</subject><subject>Fibrosis</subject><subject>Food, Formulated</subject><subject>Gastroenterology</subject><subject>Growth factors</subject><subject>Heparan sulfate proteoglycans</subject><subject>Hepatocellular carcinoma</subject><subject>Hepatology</subject><subject>Inflammation</subject><subject>Insulin</subject><subject>Insulin resistance</subject><subject>Insulin Resistance - physiology</subject><subject>Insulin-Like Growth Factor II - metabolism</subject><subject>Insulin-like growth factors</subject><subject>Liver</subject><subject>Liver cancer</subject><subject>Liver cirrhosis</subject><subject>Liver diseases</subject><subject>Liver Neoplasms - etiology</subject><subject>Medicine and Health Sciences</subject><subject>Metabolic disorders</subject><subject>Metabolic syndrome</subject><subject>Mice</subject><subject>Non-alcoholic Fatty Liver Disease - complications</subject><subject>Non-alcoholic Fatty Liver Disease - physiopathology</subject><subject>Nutrient deficiency</subject><subject>Obesity</subject><subject>Osteopontin</subject><subject>Osteopontin - metabolism</subject><subject>Pathogenesis</subject><subject>Physiology</subject><subject>Proto-Oncogene Proteins c-myc - metabolism</subject><subject>Research and Analysis 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Protozoology Abstracts (Microbiology C)</collection><collection>Biological Science Database</collection><collection>Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>De Minicis, Samuele</au><au>Agostinelli, Laura</au><au>Rychlicki, Chiara</au><au>Sorice, Gian Pio</au><au>Saccomanno, Stefania</au><au>Candelaresi, Cinzia</au><au>Giaccari, Andrea</au><au>Trozzi, Luciano</au><au>Pierantonelli, Irene</au><au>Mingarelli, Eleonora</au><au>Marzioni, Marco</au><au>Muscogiuri, Giovanna</au><au>Gaggini, Melania</au><au>Benedetti, Antonio</au><au>Gastaldelli, Amalia</au><au>Guido, Maria</au><au>Svegliati-Baroni, Gianluca</au><au>Bartosch, Birke</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>HCC development is associated to peripheral insulin resistance in a mouse model of NASH</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2014-05-22</date><risdate>2014</risdate><volume>9</volume><issue>5</issue><spage>e97136</spage><pages>e97136-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>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.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24853141</pmid><doi>10.1371/journal.pone.0097136</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2014-05, Vol.9 (5), p.e97136 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1527403424 |
| source | MEDLINE; DOAJ Directory of Open Access Journals; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Public Library of Science (PLoS); PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Age Factors AKT protein Amino acids Analysis Animals Biocompatibility Biology and Life Sciences Biomedical materials c-Myc protein Carbon tetrachloride Carcinogenesis Carcinogens Carcinoma, Hepatocellular - etiology Choline Choline Deficiency Cirrhosis Diabetes Diet Disease Models, Animal Endocrinology Fibrosis Food, Formulated Gastroenterology Growth factors Heparan sulfate proteoglycans Hepatocellular carcinoma Hepatology Inflammation Insulin Insulin resistance Insulin Resistance - physiology Insulin-Like Growth Factor II - metabolism Insulin-like growth factors Liver Liver cancer Liver cirrhosis Liver diseases Liver Neoplasms - etiology Medicine and Health Sciences Metabolic disorders Metabolic syndrome Mice Non-alcoholic Fatty Liver Disease - complications Non-alcoholic Fatty Liver Disease - physiopathology Nutrient deficiency Obesity Osteopontin Osteopontin - metabolism Pathogenesis Physiology Proto-Oncogene Proteins c-myc - metabolism Research and Analysis Methods Rodents Steatosis Tumors |
| title | HCC development is associated to peripheral insulin resistance in a mouse model of NASH |
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