title: Enhanced prereceptor glucocorticoid metabolism and lipogenesis impair insulin signaling in the liver of fructose-fed rats.
abstract: Overconsumption of fructose, as a highly lipogenic sugar, may profoundly affect hepatic metabolism and has been associated with many components of the metabolic syndrome, particularly with insulin resistance and Type 2 diabetes. In this study, we proposed that high fructose diet may enhance lipogenesis and decrease insulin sensitivity in the liver through dysregulation of glucocorticoid signaling. Therefore, we examined the effects of long-term consumption of 10% fructose solution on triglyceridemia, liver histology and intracellular corticosterone level, as well as on 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and hexose-6-phosphate dehydrogenase (H6PDH) mRNA and protein levels in the rat liver. Glucocorticoid action was assessed by glucocorticoid receptor (GR) expression and intracellular redistribution. We also analyzed the expression of enzymes involved in gluconeogenesis and lipogenesis, phosphoenolpyruvate carboxykinase (PEPCK) and lipin-1. The results have shown that fructose-rich diet led to increase in 11βHSD1 and H6PDH protein levels, while hepatic corticosterone concentration remained unchanged. Concomitantly, GR was increasingly accumulated in the cytoplasm, whereas its nuclear level was unchanged and accompanied by diminished PEPCK mRNA level. Elevation of lipin-1 in the liver microsomes suggested that fructose diet led to an increase in lipogenesis and consequently to hypertriglyceridemia. The observed increase of insulin receptor supstrate-1 phosphorylation on Ser(307) represents a hallmark of impaired insulin signaling in the liver of fructose-fed rat and probably is a consequence of the alterations in 11βHSD1 and lipin-1 levels. Overall, our findings suggest that fructose-rich diet may perturb hepatic prereceptor glucocorticoid metabolism and lipogenesis, resulting in hypertriglyceridemia and attenuated hepatic insulin sensitivity.
authors.affiliation: Department of Biochemistry, Institute for Biological Research "Siniša Stanković," University of Belgrade, 11000 Belgrade, Serbia.
authors.forename: Ana
authors.initials: A
authors.lastname: Vasiljević
authors.forename: Nataša
authors.initials: N
authors.lastname: Veličković
authors.forename: Biljana
authors.initials: B
authors.lastname: Bursać
authors.forename: Ana
authors.initials: A
authors.lastname: Djordjevic
authors.forename: Danijela Vojnović
authors.initials: DV
authors.lastname: Milutinović
authors.forename: Nataša
authors.initials: N
authors.lastname: Nestorović
authors.forename: Gordana
authors.initials: G
authors.lastname: Matić
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism; D000818:Animals; D002237:Carbohydrate Dehydrogenases / Q000378:metabolism; D003345:Corticosterone / Q000378:metabolism; D004040:Dietary Carbohydrates / Q000009:adverse effects*; D005632:Fructose / Q000008:administration & dosage*; D005938:Glucocorticoids / Q000378:metabolism*; D007328:Insulin / Q000502:physiology*; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014280:Triglycerides / Q000097:blood
chemical_list: D004040:Dietary Carbohydrates; D005938:Glucocorticoids; D007328:Insulin; C530902:Lpin1 protein, rat; D009687:Nuclear Proteins; D011965:Receptors, Glucocorticoid; D014280:Triglycerides; D005632:Fructose; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D003345:Corticosterone
keywords: 11βHSD1; Fructose; Glucocorticoids; Lipogenesis; Liver