title: Western diet in ApoE-LDLR double-deficient mouse model of atherosclerosis leads to hepatic steatosis, fibrosis, and tumorigenesis.
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.
authors.affiliation: Department of Radiology, Justus-Liebig University Giessen, Giessen, Germany.
authors.forename: Marian
authors.initials: M
authors.lastname: Kampschulte
authors.affiliation: Department of Radiology, Justus-Liebig University Giessen, Giessen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Stöckl
authors.affiliation: Department of Diagnostic and Interventional Radiology, BG Trauma Hospital, Frankfurt/Main, Germany.
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Langheinrich
authors.affiliation: Department of Radiology, Justus-Liebig University Giessen, Giessen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Althöhn
authors.affiliation: Department of Pathology, Saarland University, Homburg, Germany.
authors.forename: Rainer M
authors.initials: RM
authors.lastname: Bohle
authors.affiliation: Department of Radiology, Justus-Liebig University Giessen, Giessen, Germany.
authors.forename: Gabriele A
authors.initials: GA
authors.lastname: Krombach
authors.affiliation: Department of Cardiology, Angiology and Pneumology, Otto von Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Stieger
authors.affiliation: Department of Gastroenterology, Justus-Liebig University Giessen, Giessen, Germany.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Churin
authors.affiliation: Department of Gastroenterology, Justus-Liebig University Giessen, Giessen, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Kremer
authors.affiliation: MVZ for Pathology, Trier, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Dierkes
authors.affiliation: 1] Department of Gastroenterology, Justus-Liebig University Giessen, Giessen, Germany [2] Department of Medicine 1, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Rath
authors.affiliation: Department of Gastroenterology, Justus-Liebig University Giessen, Giessen, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Roeb
authors.affiliation: Department of Gastroenterology, Justus-Liebig University Giessen, Giessen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Roderfeld
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000150:complications* / Q000235:genetics; D066273:Diet, Western / Q000009:adverse effects*; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000209:etiology*; D050356:Lipid Metabolism; D008103:Liver Cirrhosis / Q000150:complications*; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000000981:diagnostic imaging / Q000209:etiology*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics; D015398:Signal Transduction; D055114:X-Ray Microtomography
chemical_list: D001057:Apolipoproteins E; D011973:Receptors, LDL