title: Reduced expression of peroxisome proliferator-activated receptor-alpha may have an important role in the development of non-alcoholic fatty liver disease.
abstract: BACKGROUND
  Although the pathogenesis of non-alcoholic fatty liver disease (NAFLD) remains poorly understood, metabolic syndrome associated with insulin resistance is the most reproducible factor in the development of NAFLD. Fat accumulation in hepatocytes results from an imbalance in the input, output and oxidation of fatty acid. Peroxisomes contain a battery of fatty acid oxidizing enzymes, the first of which, acyl-CoA oxidase (AOX), initiates the beta-oxidation spiral. One of the mammalian peroxisome proliferator-activated receptors (PPAR), PPAR-alpha, regulates the transcriptional expression of the enzymes involved in fatty acid beta-oxidation. The aim of the present study was to define the role of PPAR-alpha and AOX in the development of NAFLD using the Otsuka Long-Evans Tokushima fatty (OLETF) rat model.
  
  
  METHODS
  Liver tissue from OLETF (n = 12) and control (n = 10) rats 12, 28, and 40 weeks old were processed for histopathological and western blot analysis. The messenger RNA of PPAR-alpha and AOX were quantified by real-time RT-PCR.
  
  
  RESULTS
  At 40 weeks old, the histological analysis of the OLETF rat liver had steatosis (approximately 66%) and mild inflammation, which were comparable to those in NAFLD. Histological changes were unremarkable in 12 week and 28 week rats. In 12 week OLETF rats, the mRNA of AOX was 63% of the control. Expression of PPAR-alpha mRNA was also reduced to 3% that of the control. Along with the changes of mRNA, the protein expression of PPAR-alpha was also significantly reduced to 17% that of the control. In 28 week and 40 week animals, PPAR-alpha protein expression gradually increased to 75% and 78% that of the control. Expression of PPAR-alpha mRNA was also increased by up to 26% and 110% of the control. AOX, regulated by PPAR-alpha, also increased to 149% and 120% of the control.
  
  
  CONCLUSIONS
  Reduced expression of PPAR-alpha and AOX was observed even before definite steatosis had developed. The alteration of peroxisomal fatty acid metabolism may have an important role in the development of NAFLD.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Korea. je_yeon@hotmail.com
authors.forename: Jong Eun
authors.initials: JE
authors.lastname: Yeon
authors.forename: Kyung Mook
authors.initials: KM
authors.lastname: Choi
authors.forename: Sei Hyun
authors.initials: SH
authors.lastname: Baik
authors.forename: Kyoung Oh
authors.initials: KO
authors.lastname: Kim
authors.forename: Hyoung Joon
authors.initials: HJ
authors.lastname: Lim
authors.forename: Ki Ho
authors.initials: KH
authors.lastname: Park
authors.forename: Jin Yong
authors.initials: JY
authors.lastname: Kim
authors.forename: Jong-Jae
authors.initials: JJ
authors.lastname: Park
authors.forename: Jae Seon
authors.initials: JS
authors.lastname: Kim
authors.forename: Young-Tae
authors.initials: YT
authors.lastname: Bak
authors.forename: Kwan Soo
authors.initials: KS
authors.lastname: Byun
authors.forename: Chang Hong
authors.initials: CH
authors.lastname: Lee
mesh_terms: D042962:Acyl-CoA Oxidase / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D047493:PPAR alpha / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D005227:Fatty Acids; D047493:PPAR alpha; D012333:RNA, Messenger; D042962:Acyl-CoA Oxidase