Comparison of Gene Expression Patterns Between Mouse Models of Nonalcoholic Fatty Liver Disease and Liver Tissues From Patients.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in industrialized countries. Mouse models of NAFLD have been used in studies of pathogenesis and treatment, and have certain features of the human disease. We performed a systematic transcriptome-wide analysis of liver tissues from patients at different stages of NAFLD progression (ranging from healthy obese individuals to those with steatosis), as well as rodent models of NAFLD, to identify those that most closely resemble human disease progression in terms of gene expression patterns.



We performed a systematic evaluation of genome-wide messenger RNA expression using liver tissues collected from mice fed a standard chow diet (controls) and 9 mouse models of NAFLD: mice on a high-fat diet (with or without fructose), mice on a Western-type diet, mice on a methionine- and choline-deficient diet, mice on a high-fat diet given streptozotocin, and mice with disruption of Pten in hepatocytes. We compared gene expression patterns with those of liver tissues from 25 patients with nonalcoholic steatohepatitis (NASH), 27 patients with NAFLD, 15 healthy obese individuals, and 39 healthy nonobese individuals (controls). Liver samples were obtained from patients undergoing liver biopsy for suspected NAFLD or NASH, or during liver or bariatric surgeries. Data sets were analyzed using the limma R-package. Overlap of functional profiles was analyzed by gene set enrichment analysis profiles.



We found differences between human and mouse transcriptomes to be significantly larger than differences between disease stages or models. Of the 65 genes with significantly altered expression in patients with NASH and 177 genes with significantly altered expression in patients with NAFLD, compared with controls, only 1-18 of these genes also differed significantly in expression between mouse models of NAFLD and control mice. However, expression of genes that regulate pathways associated with the development of NAFLD were altered in some mouse models (such as pathways associated with lipid metabolism). On a pathway level, gene expression patterns in livers of mice on the high-fat diet were associated more closely with human fatty liver disease than other models.



In comparing gene expression profiles between liver tissues from different mouse models of NAFLD and patients with different stages of NAFLD, we found very little overlap. Our data set is available for studies of pathways that contribute to the development of NASH and NAFLD and selection of the most applicable mouse models (http://www.nash-profiler.com).
Department of Medicine I, University Hospital, Regensburg, Germany. Electronic address: andreas.teufel@ukr.de.
Andreas
A
Teufel
Department of Medicine I, University Hospital, Regensburg, Germany.
Timo
T
Itzel
Department of Internal Medicine I, University Hospital, Kiel, Germany.
Wiebke
W
Erhart
Medical Department 1, University Hospital Dresden, Technical University Dresden, Dresden, Germany.
Mario
M
Brosch
Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Mainz, Germany.
Xiao Yu
XY
Wang
Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Mainz, Germany.
Yong Ook
YO
Kim
Department of Visceral and Thoracic Surgery, University Hospital, Kiel, Germany.
Witigo
W
von Schönfels
Department of Internal Medicine I, University Hospital, Kiel, Germany.
Alexander
A
Herrmann
Medical Department 1, University Hospital Dresden, Technical University Dresden, Dresden, Germany.
Stefan
S
Brückner
Department of Clinical Research, Division of Hepatology, University of Berne, Berne, Switzerland.
Felix
F
Stickel
Department of Clinical Research, Division of Hepatology, University of Berne, Berne, Switzerland.
Jean-François
JF
Dufour
Department of Clinical Pathobiochemistry, Technical University Dresden, Dresden, Germany.
Triantafyllos
T
Chavakis
Department of Medicine I, University Hospital, Regensburg, Germany.
Claus
C
Hellerbrand
Statistical Bioinfomatics, Institute of Functional Genomics, University of Regensburg, Regensburg, Germany.
Rainer
R
Spang
Department of Medicine I, University Hospital, Regensburg, Germany.
Thorsten
T
Maass
Department of Visceral and Thoracic Surgery, University Hospital, Kiel, Germany.
Thomas
T
Becker
Department of Internal Medicine I, University Hospital, Kiel, Germany.
Stefan
S
Schreiber
Department of Visceral and Thoracic Surgery, University Hospital, Kiel, Germany.
Clemens
C
Schafmayer
Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Mainz, Germany; Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Detlef
D
Schuppan
Medical Department 1, University Hospital Dresden, Technical University Dresden, Dresden, Germany.
Jochen
J
Hampe
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001706:Biopsy; D016022:Case-Control Studies; D004032:Diet; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008099:Liver / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D013311:Streptozocin; D059467:Transcriptome / Q000235:genetics
D012333:RNA, Messenger; D013311:Streptozocin
Comparative; Cross-Species Analysis; Steatosis; Transcriptome