title: Restoration of autophagy alleviates hepatic ER stress and impaired insulin signalling transduction in high fructose-fed male mice.
abstract: High-carbohydrate (mainly fructose) consumption is a major dietary factor for hepatic insulin resistance, involving endoplasmic reticulum (ER) stress and lipid accumulation. Because autophagy has been implicated in ER stress, the present study investigated the role of autophagy in high-fructose (HFru) diet-induced hepatic ER stress and insulin resistance in male C57BL/6J mice. The results show that chronic HFru feeding induced glucose intolerance and impaired insulin signaling transduction in the liver, associated with ER stress and the accumulation of lipids. Intriguingly, hepatic autophagy was suppressed as a result of activation of mammalian target of rapamycin. The suppressed autophagy was detected within 6 hours after HFru feeding along with activation of both inositol-requiring enzyme 1 and protein kinase RNA-like endoplasmic reticulum kinase pathways. These events occurred prior to lipid accumulation or lipogenesis and were sufficient to blunt insulin signaling transduction with activation of c-Jun N-terminal kinase/inhibitory-κB kinase and serine phosphorylation of insulin receptor substrate 1. The stimulation of autophagy attenuated ER stress- and c-Jun N-terminal kinase/inhibitory-κB kinase-associated impairment in insulin signaling transduction in a mammalian target of rapamycin -independent manner. Taken together, our data suggest that restoration of autophagy functions disrupted by fructose is able to alleviate ER stress and improve insulin signaling transduction.
authors.affiliation: Lipid Biology and Metabolic Disease Laboratory, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, Victoria 3083, Australia.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Ruo-Qiong
authors.initials: RQ
authors.lastname: Sun
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Zeng
authors.forename: Xiu
authors.initials: X
authors.lastname: Zhou
authors.forename: Songpei
authors.initials: S
authors.lastname: Li
authors.forename: Eunjung
authors.initials: E
authors.lastname: Jo
authors.forename: Juan C
authors.initials: JC
authors.lastname: Molero
authors.forename: Ji-Ming
authors.initials: JM
authors.lastname: Ye
mesh_terms: D000818:Animals; D001343:Autophagy; D004040:Dietary Carbohydrates / Q000633:toxicity; D004721:Endoplasmic Reticulum / Q000502:physiology*; D005632:Fructose / Q000633:toxicity*; D018149:Glucose Intolerance; D007328:Insulin / Q000378:metabolism*; D050155:Lipogenesis; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D048670:MAP Kinase Kinase 4; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013312:Stress, Physiological / Q000502:physiology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D004040:Dietary Carbohydrates; D007328:Insulin; D005632:Fructose; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D048670:MAP Kinase Kinase 4