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Am J Physiol Endocrinol Metab 282: E1180-E1190, 2002. First published January 22, 2002; doi:10.1152/ajpendo.00471.2001
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Vol. 282, Issue 5, E1180-E1190, May 2002

Amelioration of high fructose-induced metabolic derangements by activation of PPARalpha

Yoshio Nagai1, Yoshihiko Nishio1, Takaaki Nakamura2, Hiroshi Maegawa1, Ryuichi Kikkawa1, and Atsunori Kashiwagi1

1 Third Department of Medicine and 2 Department of Anatomy, Shiga University of Medical Science, Seta, Otsu, Shiga 520-2192, Japan

To elucidate molecular mechanisms of high fructose-induced metabolic derangements and the influence of peroxisome proliferator-activated receptor-alpha (PPARalpha ) activation on them, we examined the expression of sterol regulatory element binding protein-1 (SREBP-1) and PPARalpha as well as its nuclear activation and target gene expressions in the liver of high fructose-fed rats with or without treatment of fenofibrate. After 8-wk feeding of a diet high in fructose, the mRNA contents of PPARalpha protein and its activity and gene expressions of fatty acid oxidation enzymes were reduced. In contrast, the gene expressions of SREBP-1 and lipogenic enzymes in the liver were increased by high fructose feeding. Similar high fructose effects were also found in isolated hepatocytes exposed to 20 mM fructose in the media. The treatment of fenofibrate (30 mg · kg-1 · day-1) significantly improved high fructose-induced metabolic derangements such as insulin resistance, hypertension, hyperlipidemia, and fat accumulation in the liver. Consistently, the decreased PPARalpha protein content, its activity, and its target gene expressions found in high fructose-fed rats were all improved by fenofibrate treatment. Furthermore, we also found that the copy number of mitochondrial DNA, the expressions of mitochondrial transcription factor A, ATPase-6 subunit, and uncoupling protein-3 were increased by fenofibrate treatment. These findings suggest that the metabolic syndrome in high fructose-fed rats is reversed by fenofibrate treatment, which is associated with the induction of enzyme expression related to beta -oxidation and the enhancement of mitochondrial gene expression.

peroxisome proliferator-activated receptor-alpha ; sterol regulatory element binding protein


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