title: Advanced glycation end products promote hepatosteatosis by interfering with SCAP-SREBP pathway in fructose-drinking mice.
abstract: Clinical studies have linked the increased consumption of fructose to the development of obesity, dyslipidemia, and impaired glucose tolerance, and a role in hepatosteatosis development is presumed. Fructose can undergo a nonenzymatic reaction from which advanced glycation end products (AGEs) are derived, leading to the formation of dysfunctional, fructosylated proteins; however, the in vivo formation of AGEs from fructose is still less known than that from glucose. In the present study C57Bl/6J mice received 15% (wt/vol) fructose (FRT) or 15% (wt/vol) glucose (GLC) in water to drink for 30 wk, resembling human habit to consume sugary drinks. At the end of the protocol both FRT- and GLC-drinking mice had increased fasting glycemia, glucose intolerance, altered plasma lipid profile, and marked hepatosteatosis. FRT mice had higher hepatic triglycerides deposition than GLC, paralleled by a greater increased expression and activity of the sterol regulatory element-binding protein 1 (SREBP1), the transcription factor responsible for the de novo lipogenesis, and of its activating protein SCAP. LC-MS analysis showed a different pattern of AGE production in liver tissue between FRT and GLC mice, with larger amount of carboxymethyl lysine (CML) generated by fructose. Double immunofluorescence and coimmunoprecipitation analysis revealed an interaction between CML and SCAP that could lead to prolonged activation of SREBP1. Overall, the high levels of CML and activation of SCAP/SREBP pathway associated to high fructose exposure here reported may suggest a key role of this signaling pathway in mediating fructose-induced lipogenesis.
authors.affiliation: Dept. of Clinical and Biological Sciences, Experimental Medicine and Clinical Pathology Unit, Univ. of Turin, C.so Raffaello 30, 10125 Torino, Italy. raffaella.mastrocola@unito.it.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Mastrocola
authors.forename: Massimo
authors.initials: M
authors.lastname: Collino
authors.forename: Mara
authors.initials: M
authors.lastname: Rogazzo
authors.forename: Claudio
authors.initials: C
authors.lastname: Medana
authors.forename: Debora
authors.initials: D
authors.lastname: Nigro
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Boccuzzi
authors.forename: Manuela
authors.initials: M
authors.lastname: Aragno
mesh_terms: D000818:Animals; D004326:Drinking; D005234:Fatty Liver / Q000139:chemically induced* / Q000378:metabolism; D005632:Fructose / Q000378:metabolism / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D018149:Glucose Intolerance / Q000139:chemically induced / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism / Q000633:toxicity*; D007003:Hypoglycemia / Q000139:chemically induced / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D017127:Glycation End Products, Advanced; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D008565:Membrane Proteins; C102196:SREBP cleavage-activating protein; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D005632:Fructose; C048496:N(6)-carboxymethyllysine; D005947:Glucose; D008239:Lysine
keywords: AGEs; SREBP; carboxymethyl lysine; fructose; glucose; hepatosteatosis; soft drink; triglyceride synthesis