title: A self-defeating anabolic program leads to β-cell apoptosis in endoplasmic reticulum stress-induced diabetes via regulation of amino acid flux.
abstract: Endoplasmic reticulum (ER) stress-induced responses are associated with the loss of insulin-producing β-cells in type 2 diabetes mellitus. β-Cell survival during ER stress is believed to depend on decreased protein synthesis rates that are mediated via phosphorylation of the translation initiation factor eIF2α. It is reported here that chronic ER stress correlated with increased islet protein synthesis and apoptosis in β-cells in vivo. Paradoxically, chronic ER stress in β-cells induced an anabolic transcription program to overcome translational repression by eIF2α phosphorylation. This program included expression of amino acid transporter and aminoacyl-tRNA synthetase genes downstream of the stress-induced ATF4-mediated transcription program. The anabolic response was associated with increased amino acid flux and charging of tRNAs for branched chain and aromatic amino acids (e.g. leucine and tryptophan), the levels of which are early serum indicators of diabetes. We conclude that regulation of amino acid transport in β-cells during ER stress involves responses leading to increased protein synthesis, which can be protective during acute stress but can lead to apoptosis during chronic stress. These studies suggest that the increased expression of amino acid transporters in islets can serve as early diagnostic biomarkers for the development of diabetes.
authors: Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106, USA. krokud@gmail.com
authors: Dawid
authors: D
authors: Krokowski
authors: Jaeseok
authors: J
authors: Han
authors: Mridusmita
authors: M
authors: Saikia
authors: Mithu
authors: M
authors: Majumder
authors: Celvie L
authors: CL
authors: Yuan
authors: Bo-Jhih
authors: BJ
authors: Guan
authors: Elena
authors: E
authors: Bevilacqua
authors: Ovidio
authors: O
authors: Bussolati
authors: Stefan
authors: S
authors: Bröer
authors: Peter
authors: P
authors: Arvan
authors: Marek
authors: M
authors: Tchórzewski
authors: Martin D
authors: MD
authors: Snider
authors: Michelle
authors: M
authors: Puchowicz
authors: Colleen M
authors: CM
authors: Croniger
authors: Scot R
authors: SR
authors: Kimball
authors: Tao
authors: T
authors: Pan
authors: Antonis E
authors: AE
authors: Koromilas
authors: Randal J
authors: RJ
authors: Kaufman
authors: Maria
authors: M
authors: Hatzoglou
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism; D026905:Amino Acid Transport Systems / Q000235:genetics / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D014176:Protein Biosynthesis; D011499:Protein Processing, Post-Translational; D012343:RNA, Transfer / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D026905:Amino Acid Transport Systems; D000596:Amino Acids; C081452:Atf4 protein, mouse; D015852:Eukaryotic Initiation Factor-2; D051701:Activating Transcription Factor 4; D012343:RNA, Transfer; D000604:Amino Acyl-tRNA Synthetases
keywords: Amino Acid Transport; Aminoacyl tRNA Synthetase; Beta Cell; Diabetes; ER Stress; Glutamine
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