Reduced expression of peroxisome proliferator-activated receptor-alpha may have an important role in the development of non-alcoholic fatty liver disease.
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.
Yeon
Jong Eun
JE
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Korea University Guro Hospital, Seoul, Korea. je_yeon@hotmail.com
Choi
Kyung Mook
KM
Baik
Sei Hyun
SH
Kim
Kyoung Oh
KO
Lim
Hyoung Joon
HJ
Park
Ki Ho
KH
Kim
Jin Yong
JY
Park
Jong-Jae
JJ
Kim
Jae Seon
JS
Bak
Young-Tae
YT
Byun
Kwan Soo
KS
Lee
Chang Hong
CH
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
D005227:Fatty Acids; D047493:PPAR alpha; D012333:RNA, Messenger; D042962:Acyl-CoA Oxidase