The Genetic Architecture of Diet-Induced Hepatic Fibrosis in Mice

Autor: Calvin Pan, Samuel Canizales-Quinteros, Clara E. Magyar, Adriana Huertas-Vazquez, Karthickeyan Chella Krishnan, Zeyneb Kurt, Simon W. Beaven, Samuel W. French, Paola León-Mimila, Nahum Méndez-Sánchez, Frode Norheim, Richard C. Davis, Luis Macías-Kauffer, Iina Tuominen, Simon Sabir, Xia Yang, Francisco Campos-Pérez, Aldons J. Lusis, Darwin L Dirks, Simon T. Hui
Rok vydání: 2018
Předmět:
0301 basic medicine
Liver Cirrhosis
Male
Apolipoprotein E3
Genome-wide association study
Medical Biochemistry and Metabolomics
Inbred C57BL
Transgenic
chemistry.chemical_compound
Mice
Fibrosis
Non-alcoholic Fatty Liver Disease
Amino Acids
biology
Fatty Acids
3. Good health
Cholesterol
Liver
Female
medicine.medical_specialty
Transgene
Clinical Sciences
Immunology
Mice
Transgenic
Hyperlipidemias
03 medical and health sciences
Internal medicine
Genetic variation
Cholesterylester transfer protein
medicine
Animals
Humans
Hepatology
Gastroenterology & Hepatology
Animal
Gene Expression Profiling
medicine.disease
Dietary Fats
Cholesterol Ester Transfer Proteins
Mice
Inbred C57BL
Disease Models
Animal
030104 developmental biology
Endocrinology
chemistry
Disease Models
biology.protein
Steatosis
Hepatic fibrosis
Genome-Wide Association Study
Zdroj: Hepatology (Baltimore, Md.), vol 68, iss 6
ISSN: 0270-9139
Popis: We report the genetic analysis of a "humanized" hyperlipidemic mouse model for progressive nonalcoholic steatohepatitis (NASH) and fibrosis. Mice carrying transgenes for human apolipoprotein E*3-Leiden and cholesteryl ester transfer protein and fed a "Western" diet were studied on the genetic backgrounds of over 100 inbred mouse strains. The mice developed hepatic inflammation and fibrosis that was highly dependent on genetic background, with vast differences in the degree of fibrosis. Histological analysis showed features characteristic of human NASH, including macrovesicular steatosis, hepatocellular ballooning, inflammatory foci, and pericellular collagen deposition. Time course experiments indicated that while hepatic triglyceride levels increased steadily on the diet, hepatic fibrosis occurred at about 12 weeks. We found that the genetic variation predisposing to NASH and fibrosis differs markedly from that predisposing to simple steatosis, consistent with a multistep model in which distinct genetic factors are involved. Moreover, genome-wide association identified distinct genetic loci contributing to steatosis and NASH. Finally, we used hepatic expression data from the mouse panel and from 68 bariatric surgery patients with normal liver, steatosis, or NASH to identify enriched biological pathways. Conclusion: The pathways showed substantial overlap between our mouse model and the human disease.
Databáze: OpenAIRE
Externí odkaz: