title: Hepatic inflammation induced by high-fructose diet is associated with altered 11βHSD1 expression in the liver of Wistar rats.
abstract: OBJECTIVE
  High fructose consumption provokes metabolic perturbations that result in chronic low-grade inflammation and insulin resistance. Glucocorticoids, potent anti-inflammatory hormones, have important role in pathogenesis of diet-induced metabolic disturbances. The aim of this study was to examine the link between glucocorticoid metabolism and inflammation in the liver of fructose-fed rats.
  
  
  METHODS
  Fructose-fed male Wistar rats consumed 60% fructose solution for 9 weeks. Glucocorticoid prereceptor metabolism and signaling were analyzed by measuring the level of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) and hexose-6-phosphate dehydrogenase expression, as well as via determination of intracellular corticosterone concentration, glucocorticoid receptor subcellular distribution and expression of its target gene, phosphoenolpyruvate carboxykinase. Nuclear factor kappa B (NFκB), tumor necrosis factor alpha (TNFα) and the level of inhibitory phosphorylation of insulin receptor substrate-1 (IRS-1) on Ser(307) were analyzed as markers of hepatic inflammation. The protein and/or mRNA levels of all examined molecules were assessed by Western blot and/or qPCR.
  
  
  RESULTS
  Fructose-rich diet led to an enhancement of 11βHSD1 protein level in the liver, without affecting intracellular level of corticosterone and downstream glucocorticoid signaling. On the other hand, proinflammatory state was achieved through NFκB activation and increased TNFα expression, while elevated level of inhibitory phosphorylation of IRS-1 was observed as an early hallmark of insulin resistance.
  
  
  CONCLUSIONS
  High-fructose diet does not influence hepatic glucocorticoid signaling downstream of the receptor, permitting development of NFκB-driven inflammation. The alteration in 11βHSD1 expression is most likely the consequence of enhanced inflammation, finally leading to disruption of insulin signaling in the rat liver.
authors.affiliation: Department of Biochemistry, Institute for Biological Research "Siniša Stanković", University of Belgrade, 142 Despot Stefan Blvd., 11000, Belgrade, Serbia.
authors.forename: Ana
authors.initials: A
authors.lastname: Vasiljević
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: Marina
authors.initials: M
authors.lastname: Nikolić
authors.forename: Gordana
authors.initials: G
authors.lastname: Matić
authors.forename: Nataša
authors.initials: N
authors.lastname: Veličković
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002237:Carbohydrate Dehydrogenases / Q000235:genetics / Q000378:metabolism; D002149:Energy Intake; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005632:Fructose / Q000008:administration & dosage* / Q000009:adverse effects; D005938:Glucocorticoids / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology*; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D005938:Glucocorticoids; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D016328:NF-kappa B; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D005632:Fructose; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1