Transcriptional networks in a rat model for nonalcoholic fatty liver disease: a microarray analysis.
BACKGROUND
Nonalcoholic fatty liver disease (NAFLD) is a common hepatic condition that may progress to end-stage liver disease. High-fat diets in animals reproduce many of the features found in nonalcoholic steatohepatitis.


OBJECTIVE
To understand how various dietary or genetic factors influence the development of fatty liver and consequently NAFLD, we performed microarray-based expression profiling of genes, induced by fish oil and dextrose diet, a putative mediator of alcohol-like effects on the liver of the female rat.


METHODS
Male and age-matched female rats were fed fish oil and dextrose for 4 weeks. Hepatic RNA from each sample was extracted and used for microarray analysis.


RESULTS
A large number of genes underwent significant changes in the female liver as compared to male controls. In the female rat liver, biological theme analysis demonstrated a shift in the transcriptional program which included upregulation of genes involved in lipid metabolism, chaperone activity, mitochondrial and oxidoreductase activity combined with downregulation of genes involved in nucleic acid metabolism. The differential expression of genes of interest identified by microarray technique was validated by real-time reverse transcription-polymerase chain reaction. Ingenuity computational pathway analysis tools were used to identify specific regulatory networks of genes operative in promoting liver injury.


CONCLUSIONS
The use of networks stated above allowed us to identify genes involved in cell death, apoptosis, peroxisome proliferator-activated receptor alpha-regulated lipid metabolism and mitogen-activated protein kinase signaling pathways.
Sharma
Meena R
MR
Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, A-414 VA Medical Center, Woodland Avenue, Philadelphia, PA 19104, USA. prasunsh@mail.med.upenn.edu <prasunsh@mail.med.upenn.edu>
Polavarapu
Rathnagiri
R
Roseman
Daniel
D
Patel
Viraj
V
Eaton
Eric
E
Kishor
P B Kavi
PB
Nanji
Amin A
AA
D000818:Animals; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000235:genetics; D005234:Fatty Liver / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks / Q000235:genetics*; D007249:Inflammation; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress / Q000235:genetics; D047493:PPAR alpha / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000235:genetics; D051720:Upstream Stimulatory Factors / Q000235:genetics
D016207:Cytokines; D047493:PPAR alpha; D012333:RNA, Messenger; D051720:Upstream Stimulatory Factors; C497187:Usf2 protein, rat