Reduced expression of peroxisome proliferator-activated receptor-α may have an important role in the development of non-alcoholic fatty liver disease.

Jong Eun Yeon; Kyung Mook Choi; Sei Hyun Baik; Kyoung Oh Kim; Hyoung Joon Lim; Ki Ho Park; Jin Yong Kim; Jong-Jae Park; Jae Seon Kim; Young-Tae Bak; Kwan Soo Byun; Chang Hong Lee

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 β-oxidation spiral. One of the mammalian peroxisome proliferator-activated receptors (PPAR), PPAR-α, regulates the transcriptional expression of the enzymes involved in fatty acid β-oxidation. The aim of the present study was to define the role of PPAR-α and AOX in the development of NAFLD using the Otsuka Long-Evans Tokushima fatty (OLETF) rat model. 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-α and AOX were quantified by real-time RT-PCR. 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-α mRNA was also reduced to 3% that of the control. Along with the changes of mRNA, the protein expression of PPAR-α was also significantly reduced to 17% that of the control. In 28 week and 40 week animals, PPAR-α protein expression gradually increased to 75% and 78% that of the control. Expression of PPAR-α mRNA was also increased by up to 26% and 110% of the control. AOX, regulated by PPAR-α, also increased to 149% and 120% of the control. Reduced expression of PPAR-α 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. © 2004 Blackwell Publishing Asia Pty Ltd

PEROXISOMES; LIVER diseases; INSULIN resistance; LIVER cells; HISTOPATHOLOGY; MESSENGER RNA

Journal of Gastroenterology & Hepatology, 2004, Vol 19, Issue 7, p799

0815-9319

Academic Journal

10.1111/j.1440-1746.2004.03349.x