High dietary fructose induces a hepatic stress response resulting in cholesterol and lipid dysregulation.
High-fructose feeding causes diet-induced alterations of lipid metabolism and decreased insulin sensitivity with alterations of hepatic pyruvate dehydrogenase and hepatic very low-density lipoprotein secretion. Inflammatory cytokines also induce dramatic changes in lipid metabolism, particularly in serum triglycerides via increased hepatic secretion and/or delayed clearance of very low-density lipoprotein. The aim of this study was to determine whether 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 d to establish hypertriglyceridemia and then were treated with lipoxygenase inhibitors for 4 d concurrent with the diet. At the end of drug treatment, the animals were divided into two groups and treated with lipopolysaccharide or a vehicle. Serum samples were taken pretreatment and posttreatment, 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 c-Jun N-terminal kinase pathway with correspondingly elevated activator protein-1 activity, consistent with an inflammatory response. Treatment with lipoxygenase inhibitors reversed the hypertriglyceridemia and also reduced activator protein-1 activation, suggesting that the basis for lipid dysregulation in this model is due to activation of inflammatory pathways in the liver.
Kelley
Glen L
GL
Insmed Incorporated, 4851 Lake Brook Drive, Glen Allen, VA 23058, USA. gkelley@insmed.com
Allan
Geoffrey
G
Azhar
Salman
S
D000210:Acute-Phase Reaction / Q000209:etiology; D000818:Animals; D003345:Corticosterone / Q000097:blood; D004040:Dietary Carbohydrates / Q000008:administration & dosage*; D005632:Fructose / Q000008:administration & dosage*; D006937:Hypercholesterolemia / Q000209:etiology* / Q000517:prevention & control; D015228:Hypertriglyceridemia / Q000209:etiology* / Q000517:prevention & control; D048031:JNK Mitogen-Activated Protein Kinases; D050356:Lipid Metabolism; D015227:Lipid Peroxidation; D008070:Lipopolysaccharides / Q000494:pharmacology; D008079:Lipoproteins, VLDL / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
D004040:Dietary Carbohydrates; D008070:Lipopolysaccharides; D008079:Lipoproteins, VLDL; D016859:Lipoxygenase Inhibitors; D011768:Pyruvate Dehydrogenase Complex; D017392:Thiobarbituric Acid Reactive Substances; D005632:Fructose; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D003345:Corticosterone