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Am J Physiol Endocrinol Metab (January 22, 2002). doi:10.1152/ajpendo.00471.2001
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Articles in PresS, published online ahead of print January 22, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00471.2001
Submitted on October 18, 2001
Accepted on December 14, 2001

Amelioration of high fructose-induced metabolic derangements by activation of PPAR-{alpha}

Yoshio Nagai1, Yoshihiko Nishio1, Takaaki Nakamura2, Hiroshi Maegawa1, Ryuichi Kikkawq1, and Atsunori Kashiwagi1*

1 Third Department of Medicine, Shiga University of Medical Science, Otsu, Shiga, Japan
2 Department of Anatomy, Shiga University of Medical Science, Otsu, Shiga, Japan

* To whom correspondence should be addressed. E-mail: kasiwagi{at}belle.shiga-med.ac.jp.

To elucidate molecular mechanisms of high fructose-induced metabolic derangements as well as the influence of peroxisome proliferator-activated receptor-{alpha} (PPAR-{alpha} activation on them, we examined the expression of sterol regulatory element binding protein-1 (SREBP-1) and PPAR-{alpha} 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-weeks feeding of a diet high in fructose the mRNA contents of PPAR-{alpha} 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/day) significantly improved high fructose-induced metabolic derangements such as insulin resistance, hypertension, hyperlipidemia, and fat accumulation in the liver. Consistently, the decreased PPAR-{alpha} 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 the fenofibrate treatment. These findings suggest that the metabolic syndrome in high fructose-fed rats is reversed by the fenofibrate treatment, which is associated with the induction of enzyme expression related to ß-oxidation as well as the enhancement of mitochondrial gene expression.




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