title: IRE1 impairs insulin signaling transduction of fructose-fed mice via JNK independent of excess lipid.
abstract: The unfolded protein response (UPR) pathways have been implicated in the development of hepatic insulin resistance during high fructose (HFru) feeding. The present study investigated their roles in initiating impaired insulin signaling transduction in the liver induced by HFru feeding in mice. HFru feeding resulted in hepatic steatosis, increased de novo lipogenesis and activation of two arms of the UPR pathways (IRE1/XBP1 and PERK/eIF2α) in similar patterns from 3days to 8weeks. In order to identify the earliest trigger of impaired insulin signaling in the liver, we fed mice a HFru diet for one day and revealed that only the IRE1 branch was activated (by 2-fold) and insulin-mediated Akt phosphorylation was blunted (~25%) in the liver. There were significant increases in phosphorylation of JNK (~50%) and IRS at serine site (~50%), protein content of ACC and FAS (up to 2.5-fold) and triglyceride level (2-fold) in liver (but not in muscle or fat). Blocking IRE1 activity abolished increases in JNK activity, IRS serine phosphorylation and protected insulin-stimulated Akt phosphorylation without altering hepatic steatosis or PKCε activity, a key link between lipids and insulin resistance. Our findings together suggest that activation of IRE1-JNK pathway is a key linker of impaired hepatic insulin signaling transduction induced by HFru feeding.
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Ruo-Qiong
authors.initials: RQ
authors.lastname: Sun
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Zeng
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Stanley M H
authors.initials: SM
authors.lastname: Chan
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Song-Pei
authors.initials: SP
authors.lastname: Li
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Jo
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Sit-Lam
authors.initials: SL
authors.lastname: Leung
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Molero
authors.affiliation: Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia. Electronic address: jiming.ye@rmit.edu.au.
authors.forename: Ji-Ming
authors.initials: JM
authors.lastname: Ye
mesh_terms: D000818:Animals; D005632:Fructose / Q000008:administration & dosage* / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014280:Triglycerides / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D007328:Insulin; D008565:Membrane Proteins; D014280:Triglycerides; D005632:Fructose; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Hepatic steatosis; High carbohydrate diet; Insulin signaling; UPR signaling pathways