title: Extracellular matrix and cytochrome P450 gene expression can distinguish steatohepatitis from steatosis in mice.
abstract: One of the main questions regarding nonalcoholic fatty liver disease is the molecular background of the transition from simple steatosis (SS) to the inflammatory and fibrogenic condition of steatohepatitis (NASH). We examined the gene expression changes during progression from histologically normal liver to SS and NASH in models of obesity caused by hyperphagia or a high-fat diet. Microarray-based analysis revealed that the expression of 1445 and 264 probe sets was changed exclusively in SS and NASH samples, respectively, and 1577 probe sets were commonly altered in SS and NASH samples. Functional annotations indicated that transcriptome alterations that were common for NASH and SS, as well as exclusive for NASH, involved extracellular matrix (ECM)-related processes, although they differed in the type of matrix structure change. The expression of 80 genes was significantly changed in all three comparisons: SS versus control, NASH versus control and NASH versus SS. Of these genes, epithelial membrane protein 1, IKBKB interacting protein and decorin were progressively up-regulated in both SS and NASH compared to normal tissue. The molecular context of interactions of encoded 80 proteins revealed that they are highly interconnected and significantly enriched for processes involving metabolism by cytochrome P450. Validation of 10 selected mRNAs encoding genes related to ECM and cytochrome P450 with quantitative RT-PCR analysis showed consistent changes in their expression during NASH development. The expression profile of these genes has the potential to distinguish NASH from SS and normal tissue and may possibly be beneficial in the clinical diagnosis of NASH.
authors.affiliation: Department of Gastroenterology and Hepatology, Medical Center for Postgraduate Education, Warsaw, Poland; Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.
authors.forename: Ewa E
authors.initials: EE
authors.lastname: Hennig
authors.forename: Michal
authors.initials: M
authors.lastname: Mikula
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Goryca
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Paziewska
authors.forename: Joanna
authors.initials: J
authors.lastname: Ledwon
authors.forename: Monika
authors.initials: M
authors.lastname: Nesteruk
authors.forename: Marek
authors.initials: M
authors.lastname: Woszczynski
authors.forename: Bozena
authors.initials: B
authors.lastname: Walewska-Zielecka
authors.forename: Kazimiera
authors.initials: K
authors.lastname: Pysniak
authors.forename: Jerzy
authors.initials: J
authors.lastname: Ostrowski
mesh_terms: D000818:Animals; D001786:Blood Glucose; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D003937:Diagnosis, Differential; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism*; D005234:Fatty Liver / Q000175:diagnosis / Q000201:enzymology*; D006801:Humans; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D058977:Molecular Sequence Annotation; D020411:Oligonucleotide Array Sequence Analysis; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D001786:Blood Glucose; D007328:Insulin; D008055:Lipids; D003577:Cytochrome P-450 Enzyme System
keywords: NAFLD; NASH; cytochrome P450; extracellular matrix; liver; mouse model; obesity; steatohepatitis; steatosis; transcriptomics