title: Molecular pathways involved in the improvement of non-alcoholic fatty liver disease.
abstract: Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis are components of the metabolic syndrome. Serum leptin levels are elevated in obesity, but the role of leptin in the pathophysiology of the liver involvement is still unclear. To identify the effects and mechanisms by which leptin influences the pathogenesis of NAFLD, we performed epididymal white adipose tissue (eWAT) transplantation from congenic wild-type mice into the subcutaneous dorsal area of Lep(ob/ob) recipient mice and compared the results with those of the Lep(ob/ob) sham-operated mice. The mice were followed for 102-216 days. During killing, the transplanted mice had significantly lost body weight and exhibited significantly higher leptin levels, improved glucose tolerance, and lower liver injury scores than the sham-operated mice. Liver microarray analysis showed that novel pathways related to GA-binding protein (GABP) transcription factor targets, pheromone binding, and olfactory signaling were differentially expressed in the transplanted mice. Our data also replicate pathways known to be involved in NAFLD, such as those involved in the regulation of microRNAs, lipid, glucose, and glutathione metabolism, peroxisome proliferator-activated receptor signaling, cellular regulation, carboxylic acid processes, iron, heme, and tetrapyrrole binding, immunity and inflammation, insulin signaling, cytochrome P450 function, and cancer.
  
  
  CONCLUSIONS
  wild-type eWAT transplantation into Lep(ob/ob) mice led to improvements in metabolism, body weight, and liver injury, possibly attributed to the production of leptin by the transplanted eWAT. These improvements were accompanied by the differential expression of novel pathways. The causal relationship between GABP downregulation and NAFLD improvement remains to be determined.
authors.affiliation: Department of Translational Medicine, The John Curtin School of Medical Research, The Australian National University, Garran Road, Building 131, Acton, Canberra, Australian Capital Territory 0200, Australia.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Paz-Filho
authors.forename: Claudio Alberto
authors.initials: CA
authors.lastname: Mastronardi
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Parker
authors.forename: Ainy
authors.initials: A
authors.lastname: Khan
authors.forename: Antonio
authors.initials: A
authors.lastname: Inserra
authors.forename: Klaus I
authors.initials: KI
authors.lastname: Matthaei
authors.forename: Monika
authors.initials: M
authors.lastname: Ehrhart-Bornstein
authors.forename: Stefan
authors.initials: S
authors.lastname: Bornstein
authors.forename: Ma-Li
authors.initials: ML
authors.lastname: Wong
authors.forename: Julio
authors.initials: J
authors.lastname: Licinio
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism / Q000637:transplantation; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D006728:Hormones / Q000097:blood; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008822:Mice, Transgenic; D065626:Non-alcoholic Fatty Liver Disease; D015398:Signal Transduction; D013256:Steroids / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D006728:Hormones; D018836:Inflammation Mediators; D007328:Insulin; D013256:Steroids
keywords: adipose tissue; leptin; liver; microarray