Transcription factor binding site enrichment analysis predicts drivers of altered gene expression in nonalcoholic steatohepatitis.
The molecular mechanisms behind the transition from simple steatosis to nonalcoholic steatohepatitis (NASH) in nonalcoholic fatty liver disease (NAFLD) are not clearly understood. This hinders development of effective therapies for treatment and prevention of NASH. In this study expression profiling data from normal, steatosis, and NASH human livers were used to predict transcription factors that are misregulated as mechanistic features of NAFLD progression. Previously-published human NAFLD gene expression profiling data from normal, steatosis, and NASH livers were subjected to transcription factor binding site enrichment analysis. Selected transcription factors that bind enriched transcription factor binding sites were analyzed for changes in expression. Distinct transcription factor binding sites were enriched in genes significantly up- or down-regulated in NASH livers. Those enriched in up-regulated genes were bound by transcription factors such as FOXA, CEBP, and HNF1 family members, while those enriched in down-regulated genes were bound by nuclear receptors involved in xenobiotic sensing and lipid metabolism. Levels of mRNA and protein for selected transcription factors were significantly changed during disease progression. The study indicates that NAFLD progression involves changes in activity or expression of transcription factors that regulate genes involved in hepatic processes known to be altered in NASH. Transcription factors such as PPAR receptors, FoxA family members, and HNF4A might be targeted therapeutically to prevent NAFLD progression.
Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, United States.
April D
AD
Lake
Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, United States.
Alexandria L
AL
Chaput
Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, United States; Biology Centre ASCR, Institute of Plant Molecular Biology, Branisovska 31, Ceske Budejovice CZ-37005, Czech Republic.
Petr
P
Novak
Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, United States.
Nathan J
NJ
Cherrington
Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, United States. Electronic address: csmith@pharmacy.arizona.edu.
Catharine L
CL
Smith
D001665:Binding Sites; D018450:Disease Progression; D015536:Down-Regulation; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism*; D011485:Protein Binding; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
D014157:Transcription Factors
Bioinformatics; Gene expression; Liver; Metabolism; Nonalcoholic steatohepatitis; Transcription factor