title: Regulatory landscape of AGE-RAGE-oxidative stress axis and its modulation by PPARγ activation in high fructose diet-induced metabolic syndrome.
abstract: BACKGROUND
  The AGE-RAGE-oxidative stress (AROS) axis is involved in the onset and progression of metabolic syndrome induced by a high-fructose diet (HFD). PPARγ activation is known to modulate metabolic syndrome; however a systems-level investigation looking at the protective effects of PPARγ activation as related to the AROS axis has not been performed. The aim of this work is to simultaneously characterize multiple molecular parameters within the AROS axis, using samples taken from different body fluids and tissues of a rat model of HFD-induced metabolic syndrome, in the presence or absence of a PPARγ agonist, Rosiglitazone (RGZ).
  
  
  METHODS
  Rats were fed with 60% HFD for the first half of the treatment duration (21 days) then continued with either HFD alone or HFD plus RGZ for the second half.
  
  
  RESULTS
  Rats receiving HFD alone showed metabolic syndrome manifestations including hypertension, dyslipidemia, increased glucose levels and insulin resistance, as well as abnormal kidney and inflammatory parameters. Systolic blood pressure, plasma triglyceride and glucose levels, plasma creatinine, and albuminuria were significantly improved in the presence of RGZ. The following molecular parameters of the AROS axis were significantly upregulated in our rat model: carboxymethyl lysine (CML) in urine and liver; carboxyethyl lysine (CEL) in urine; advanced glycation end products (AGEs) in plasma; receptor for advanced glycation end products (RAGE) in liver and kidney; advanced oxidation protein products (AOPP) in plasma; and 4-hydroxynonenal (HNE) in plasma, liver, and kidney. Conversely, with RGZ administration, the upregulation of AOPP and AGEs in plasma, CML and CEL in urine, RAGE in liver as well as HNE in plasma and liver was significantly counteracted/prevented.
  
  
  CONCLUSIONS
  Our data demonstrate (i) the systems-level regulatory landscape of HFD-induced metabolic syndrome involving multiple molecular parameters, including HNE, AGEs and their receptor RAGE, and (ii) attenuation of metabolic syndrome by PPARγ modulation.
authors.affiliation: Systems Biology Center, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330 Thailand ; Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Cannizzaro
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Via Vanvitelli 32, 20129 Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Rossoni
authors.affiliation: Pathological Anatomy Unit (U.O.C. Anatomia Patologica), ASST Santi Paolo e Carlo, Via di Rudinì 8, 20142 Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Savi
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Altomare
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Marinello
authors.affiliation: Systems Biology Center, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330 Thailand.
authors.forename: Thammakorn
authors.initials: T
authors.lastname: Saethang
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Carini
authors.affiliation: Systems Biology Center, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330 Thailand.
authors.forename: D Michael
authors.initials: DM
authors.lastname: Payne
authors.affiliation: Systems Biology Center, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330 Thailand.
authors.forename: Trairak
authors.initials: T
authors.lastname: Pisitkun
authors.affiliation: Department of Pharmaceutical Sciences, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Aldini
authors.affiliation: Center of Excellence in Immunology and Immune-mediated Diseases, Department of Microbiology, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330 Thailand.
authors.forename: Asada
authors.initials: A
authors.lastname: Leelahavanichkul
keywords: AGE-RAGE-oxidative stress axis; Fructose; HNE; Metabolic syndrome; PPARγ; Rosiglitazone