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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-
(PPAR) activation on them, we examined the expression of sterol
regulatory element binding protein-1 (SREBP-1) and PPAR 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
PPAR 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 · day1)
significantly improved high fructose-induced metabolic derangements such as insulin resistance, hypertension, hyperlipidemia, and fat
accumulation in the liver. Consistently, the decreased PPAR 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
-oxidation and the enhancement of mitochondrial gene expression.
peroxisome proliferator-activated receptor-; sterol regulatory
element binding protein
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