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Submitted on September 4, 2003
Accepted on October 17, 2003
1 Insmed Incorporated, Richmond, Virginia, USA; Geriatric Research, Education and Clinical Center, VA Palo Alto Health Care System & Stanford University School of Medicine, Palo Alto, California, USA
* To whom correspondence should be addressed. E-mail: gkelley{at}insmed.com.
High fructose feeding causes diet-induced alterations of lipid metabolism and decreased insulin sensitivity with alterations of hepatic pyruvate dehydrogenase (1) and hepatic VLDL secretion (2). Inflammatory cytokines also induce dramatic changes in lipid metabolism, particularly in serum triglycerides via increased hepatic secretion and/or delayed clearance of VLDL (3). The aim of this study was to determine if the mechanism of lipid dysregulation in the high fructose diet is induced by stress response pathways. Animals were fed a high fructose diet for 14 days to establish hypertriglyceridemia and then were treated with lipoxygenase inhibitors for four days concurrent with the diet. At the end of drug treatment, the animals were divided into two groups and treated with LPS or a vehicle. Serum samples were taken pre-treatment and post-treatment and liver tissue was harvested at the end of study. Serum samples were tested for metabolic parameters and the tissue samples were tested for metabolic and stress pathway responses. Our results show that fructose fed rats have changes in the JNK pathway with correspondingly elevated AP-1 activity, consistent with an inflammatory response. Treatment with lipoxygenase inhibitors reversed the hypertriglyceridemia and also reduced AP-1 activation, suggesting that the basis for lipid dysregulation in this model is due to activation of inflammatory pathways in the liver.*
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