Western diet in ApoE-LDLR double-deficient mouse model of atherosclerosis leads to hepatic steatosis, fibrosis, and tumorigenesis.
Identifieur interne : 000713 ( Ncbi/Curation ); précédent : 000712; suivant : 000714Western diet in ApoE-LDLR double-deficient mouse model of atherosclerosis leads to hepatic steatosis, fibrosis, and tumorigenesis.
Auteurs : Marian Kampschulte [Allemagne] ; Christiane Stöckl [Allemagne] ; Alexander C. Langheinrich [Allemagne] ; Ulrike Althöhn [Allemagne] ; Rainer M. Bohle [Allemagne] ; Gabriele A. Krombach [Allemagne] ; Philipp Stieger [Allemagne] ; Yuri Churin [Allemagne] ; Sandra Kremer [Allemagne] ; Christian Dierkes [Allemagne] ; Timo Rath [Allemagne] ; Elke Roeb [Allemagne] ; Martin Roderfeld [Allemagne]Source :
- Laboratory investigation; a journal of technical methods and pathology [ 1530-0307 ] ; 2014.
English descriptors
- KwdEn :
- Animals, Apolipoproteins E (genetics), Atherosclerosis (complications), Atherosclerosis (genetics), Diet, Western (adverse effects), Disease Models, Animal, Fatty Liver (etiology), Lipid Metabolism, Liver Cirrhosis (complications), Liver Neoplasms, Experimental (blood supply), Liver Neoplasms, Experimental (diagnostic imaging), Liver Neoplasms, Experimental (etiology), Male, Mice, Inbred C57BL, Mice, Knockout, Receptors, LDL (genetics), Signal Transduction, X-Ray Microtomography.
- MESH :
- chemical , genetics : Apolipoproteins E, Receptors, LDL.
- adverse effects : Diet, Western.
- blood supply : Liver Neoplasms, Experimental.
- complications : Atherosclerosis, Liver Cirrhosis.
- diagnostic imaging : Liver Neoplasms, Experimental.
- etiology : Fatty Liver, Liver Neoplasms, Experimental.
- genetics : Atherosclerosis.
- Animals, Disease Models, Animal, Lipid Metabolism, Male, Mice, Inbred C57BL, Mice, Knockout, Signal Transduction, X-Ray Microtomography.
Abstract
Nonalcoholic fatty liver disease has been linked to cardiovascular diseases and atherosclerosis. The aim of the current study was to characterize the hepatic pathology leading to fibrosis and tumors in a murine model of atherosclerosis. Male apolipoprotein E/low-density lipoprotein receptor double-knockout mice (AL) mice were fed with a high fat and high cholesterol western diet for 35 weeks (AL mice on WD). Protein and mRNA analysis as well as micro-computed tomography (micro-CT) were performed to assess oxidative stress, liver damage, inflammation, fibrosis, signaling pathways, vascularization, and tumorigenesis. Controls were chosen to distinguish between genetically and dietary effects in steatohepatitis and associated tumorigenesis. Hepatic inflammation and dyslipidemia were increased in AL mice on WD compared with wild-type mice on WD. Uniquely, AL mice on WD showed a spontaneous development of tumors (30% of cases) and thickening of intrahepatic vessel walls. Functionally relevant underlying signaling pathways such as NF-κB, Stat3, JNK, and AKT were differentially regulated between AL and wild-type mice on WD. Micro-CT was capable of visualizing and quantitatively distinguishing tumor neovascularization from vascularization in non-neoplastic liver tissue. AL mice on WD diet represent a novel model combining atherosclerosis and nonalcoholic fatty liver disease. Signaling pathways of liver cell damage and compensatory liver regeneration in combination with enhanced inflammation appear to be crucial for the spontaneous development of tumors in AL mice on WD. Micro-CT represents a new and powerful technique for the ultrastructural and three-dimensional assessment of the vascular architecture of liver tumors.
DOI: 10.1038/labinvest.2014.112
PubMed: 25199052
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xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gastroenterology, Justus-Liebig University Giessen, Giessen</wicri:regionArea><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion></affiliation></author><author><name sortKey="Dierkes, Christian" sort="Dierkes, Christian" uniqKey="Dierkes C" first="Christian" last="Dierkes">Christian Dierkes</name><affiliation wicri:level="1"><nlm:affiliation>MVZ for Pathology, Trier, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>MVZ for Pathology, Trier</wicri:regionArea><wicri:noRegion>Trier</wicri:noRegion><wicri:noRegion>Trier</wicri:noRegion><wicri:noRegion>Trier</wicri:noRegion></affiliation></author><author><name sortKey="Rath, Timo" sort="Rath, Timo" uniqKey="Rath T" first="Timo" last="Rath">Timo Rath</name><affiliation wicri:level="3"><nlm:affiliation>1] Department of Gastroenterology, Justus-Liebig University Giessen, 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Giessen, Giessen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Radiology, Justus-Liebig University Giessen, Giessen</wicri:regionArea><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion></affiliation></author><author><name sortKey="Stockl, Christiane" sort="Stockl, Christiane" uniqKey="Stockl C" first="Christiane" last="Stöckl">Christiane Stöckl</name><affiliation wicri:level="1"><nlm:affiliation>Department of Radiology, Justus-Liebig University Giessen, Giessen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Radiology, Justus-Liebig University Giessen, Giessen</wicri:regionArea><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion></affiliation></author><author><name sortKey="Langheinrich, Alexander C" sort="Langheinrich, Alexander C" 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Langheinrich</name><affiliation wicri:level="3"><nlm:affiliation>Department of Diagnostic and Interventional Radiology, BG Trauma Hospital, Frankfurt/Main, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Diagnostic and Interventional Radiology, BG Trauma Hospital, Frankfurt/Main</wicri:regionArea><placeName><settlement type="city">Francfort-sur-le-Main</settlement><region type="land" nuts="1">Hesse (Land)</region><region type="district" nuts="2">District de Darmstadt</region></placeName></affiliation></author><author><name sortKey="Althohn, Ulrike" sort="Althohn, Ulrike" uniqKey="Althohn U" first="Ulrike" last="Althöhn">Ulrike Althöhn</name><affiliation wicri:level="1"><nlm:affiliation>Department of Radiology, Justus-Liebig University Giessen, Giessen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Radiology, Justus-Liebig University Giessen, Giessen</wicri:regionArea><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion></affiliation></author><author><name sortKey="Bohle, Rainer M" sort="Bohle, Rainer M" uniqKey="Bohle R" first="Rainer M" last="Bohle">Rainer M. 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Krombach</name><affiliation wicri:level="1"><nlm:affiliation>Department of Radiology, Justus-Liebig University Giessen, Giessen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Radiology, Justus-Liebig University Giessen, Giessen</wicri:regionArea><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion></affiliation></author><author><name sortKey="Stieger, Philipp" sort="Stieger, Philipp" uniqKey="Stieger P" first="Philipp" last="Stieger">Philipp Stieger</name><affiliation wicri:level="3"><nlm:affiliation>Department of Cardiology, Angiology and Pneumology, Otto von Guericke University Magdeburg, Magdeburg, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Cardiology, Angiology and Pneumology, Otto von Guericke University Magdeburg, Magdeburg</wicri:regionArea><placeName><region type="land" nuts="2">Saxe-Anhalt</region><settlement type="city">Magdebourg</settlement></placeName></affiliation></author><author><name sortKey="Churin, Yuri" sort="Churin, Yuri" uniqKey="Churin Y" first="Yuri" last="Churin">Yuri Churin</name><affiliation wicri:level="1"><nlm:affiliation>Department of Gastroenterology, Justus-Liebig University Giessen, Giessen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gastroenterology, Justus-Liebig University Giessen, Giessen</wicri:regionArea><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion></affiliation></author><author><name sortKey="Kremer, Sandra" sort="Kremer, Sandra" uniqKey="Kremer S" first="Sandra" last="Kremer">Sandra Kremer</name><affiliation wicri:level="1"><nlm:affiliation>Department of Gastroenterology, Justus-Liebig University Giessen, Giessen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gastroenterology, Justus-Liebig University Giessen, Giessen</wicri:regionArea><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion></affiliation></author><author><name sortKey="Dierkes, Christian" sort="Dierkes, Christian" uniqKey="Dierkes C" first="Christian" last="Dierkes">Christian Dierkes</name><affiliation wicri:level="1"><nlm:affiliation>MVZ for Pathology, Trier, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>MVZ for Pathology, Trier</wicri:regionArea><wicri:noRegion>Trier</wicri:noRegion><wicri:noRegion>Trier</wicri:noRegion><wicri:noRegion>Trier</wicri:noRegion></affiliation></author><author><name sortKey="Rath, Timo" sort="Rath, Timo" uniqKey="Rath T" first="Timo" last="Rath">Timo Rath</name><affiliation wicri:level="3"><nlm:affiliation>1] Department of Gastroenterology, Justus-Liebig University Giessen, Giessen, Germany [2] Department of Medicine 1, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>1] Department of Gastroenterology, Justus-Liebig University Giessen, Giessen, Germany [2] Department of Medicine 1, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen</wicri:regionArea><placeName><settlement type="city">Erlangen</settlement><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Moyenne-Franconie</region></placeName></affiliation></author><author><name sortKey="Roeb, Elke" sort="Roeb, Elke" uniqKey="Roeb E" first="Elke" last="Roeb">Elke Roeb</name><affiliation wicri:level="1"><nlm:affiliation>Department of Gastroenterology, Justus-Liebig University Giessen, Giessen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gastroenterology, Justus-Liebig University Giessen, Giessen</wicri:regionArea><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion></affiliation></author><author><name sortKey="Roderfeld, Martin" sort="Roderfeld, Martin" uniqKey="Roderfeld M" first="Martin" last="Roderfeld">Martin Roderfeld</name><affiliation wicri:level="1"><nlm:affiliation>Department of Gastroenterology, Justus-Liebig University Giessen, Giessen, Germany.</nlm:affiliation><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Gastroenterology, Justus-Liebig University Giessen, Giessen</wicri:regionArea><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion><wicri:noRegion>Giessen</wicri:noRegion></affiliation></author></analytic><series><title level="j">Laboratory investigation; a journal of technical methods and pathology</title><idno type="eISSN">1530-0307</idno><imprint><date when="2014" type="published">2014</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Animals</term><term>Apolipoproteins E (genetics)</term><term>Atherosclerosis (complications)</term><term>Atherosclerosis (genetics)</term><term>Diet, Western (adverse effects)</term><term>Disease Models, Animal</term><term>Fatty Liver (etiology)</term><term>Lipid Metabolism</term><term>Liver Cirrhosis (complications)</term><term>Liver Neoplasms, Experimental (blood supply)</term><term>Liver Neoplasms, Experimental (diagnostic imaging)</term><term>Liver Neoplasms, Experimental (etiology)</term><term>Male</term><term>Mice, Inbred C57BL</term><term>Mice, Knockout</term><term>Receptors, LDL (genetics)</term><term>Signal Transduction</term><term>X-Ray Microtomography</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Apolipoproteins E</term><term>Receptors, LDL</term></keywords><keywords scheme="MESH" qualifier="adverse effects" xml:lang="en"><term>Diet, Western</term></keywords><keywords scheme="MESH" qualifier="blood supply" xml:lang="en"><term>Liver Neoplasms, Experimental</term></keywords><keywords scheme="MESH" qualifier="complications" xml:lang="en"><term>Atherosclerosis</term><term>Liver Cirrhosis</term></keywords><keywords scheme="MESH" qualifier="diagnostic imaging" xml:lang="en"><term>Liver Neoplasms, Experimental</term></keywords><keywords scheme="MESH" qualifier="etiology" xml:lang="en"><term>Fatty Liver</term><term>Liver Neoplasms, Experimental</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Atherosclerosis</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Animals</term><term>Disease Models, Animal</term><term>Lipid Metabolism</term><term>Male</term><term>Mice, Inbred C57BL</term><term>Mice, Knockout</term><term>Signal Transduction</term><term>X-Ray Microtomography</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Nonalcoholic fatty liver disease has been linked to cardiovascular diseases and atherosclerosis. The aim of the current study was to characterize the hepatic pathology leading to fibrosis and tumors in a murine model of atherosclerosis. Male apolipoprotein E/low-density lipoprotein receptor double-knockout mice (AL) mice were fed with a high fat and high cholesterol western diet for 35 weeks (AL mice on WD). Protein and mRNA analysis as well as micro-computed tomography (micro-CT) were performed to assess oxidative stress, liver damage, inflammation, fibrosis, signaling pathways, vascularization, and tumorigenesis. Controls were chosen to distinguish between genetically and dietary effects in steatohepatitis and associated tumorigenesis. Hepatic inflammation and dyslipidemia were increased in AL mice on WD compared with wild-type mice on WD. Uniquely, AL mice on WD showed a spontaneous development of tumors (30% of cases) and thickening of intrahepatic vessel walls. Functionally relevant underlying signaling pathways such as NF-κB, Stat3, JNK, and AKT were differentially regulated between AL and wild-type mice on WD. Micro-CT was capable of visualizing and quantitatively distinguishing tumor neovascularization from vascularization in non-neoplastic liver tissue. AL mice on WD diet represent a novel model combining atherosclerosis and nonalcoholic fatty liver disease. Signaling pathways of liver cell damage and compensatory liver regeneration in combination with enhanced inflammation appear to be crucial for the spontaneous development of tumors in AL mice on WD. Micro-CT represents a new and powerful technique for the ultrastructural and three-dimensional assessment of the vascular architecture of liver tumors.</div></front></TEI></record>Pour manipuler ce document sous Unix (Dilib)
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