Beta cells are heavily engaged in the synthesis and secretion of insulin. They are therefore particularly sensitive to endoplasmic reticulum (ER) stress and the subsequent unfolded protein response (UPR). Severe or prolonged episodes of ER stress can lead to the death of beta cells,[1] which can contribute to the development of both type I and type II diabetes.[2]
ER stress in beta cells links obesity to type 2 diabetes and inflammation to type 1 diabetes.
A model of how ER stress is involved in β-cell death and type II diabetes mellitus
ER stress can be activated by a variety of factors. In experimental conditions, excessive lipid (which can happen following obesity, a common condition preceding type 2 diabetes) and pro-inflammatory cytokines (which can occur following an inflammation, a common cause for type 1 diabetes) can activate ER stress in beta cells.
Causes such as defective protein processing[4] and trafficking [5] or inappropriate calcium regulation [6] are likely in lipid-mediated ER stress. On the other hand, cytokines are likely to activate ER stress by decreasing the calcium pump Serca2b (also known as Atp2a2), leading to subsequent depletion in ER calcium stores.[7]
ER stress and inflammationedit
All three of the pathways involved in the resolution of ER stress by the unfolded protein response (UPR) are also related to inflammation.[8] The two pathways are very connected and both have been shown to activate each other[8]
Resolution of ER stressedit
Activation of ER stress by lipids results in a typical unfolded protein response (UPR) to primarily restore ER function, whereas cytokine-activated ER stress leads to an atypical UPR that preferentially activate apoptosis in beta cells.[9]
The UPR is activated when GRP78, a.k.a. BiP, a protein-folding chaperone, is recruited to assist in protein folding. In β-cells, insulin production is a major source of improperly folded protein.[1] GRP78 is normally bound to the luminal domain of ATF6, IRE1, and PERK, which prevents them from initiating their respective pathways of the UPR. When GRP78 is recruited to assist in protein folding, unbound ATF6, IRE1 and PERK are able to initiate the UPR.[10] The UPR is also activated by cytokines[8]
ER stress can be measured using quantitative real-time RT-PCR to measure the rate at which XBP1 is cleaved by IRE1 when the UPR is activated.[12] XBP1 mRNA cleavage leads to the translation of a transcription factor for genes that resolve ER stress.[10] Measuring the rate at which XBP1 is cleaved gives a quantitative measure of ER stress in real time.
Referencesedit
^ abEizirik DL, Cardozo AK, Cnop M (2008). "The role for endoplasmic reticulum stress in diabetes mellitus". Endocrine Reviews. 29 (1): 42–61. doi:10.1210/er.2007-0015. PMID 18048764.
^Wellen, Kathryn E.; Hotamisligil, Gökhan S. (2005-05-02). "Inflammation, stress, and diabetes". Journal of Clinical Investigation. 115 (5): 1111–1119. doi:10.1172/JCI25102. ISSN 0021-9738. PMC1087185. PMID 15864338.
^Jeffrey KD, Alejandro EU, Luciani DS, Kalynyak TB, Hu X, Li H, Lin Y, Townsend RR, Polonsky KS, Johnson JD (2008). "Carboxypeptidase E mediates palmitate-induced beta-cell ER stress and apoptosis". Proceedings of the National Academy of Sciences of the United States of America. 105 (24): 8452–8457. doi:10.1073/pnas.0711232105. PMC2448857. PMID 18550819.
^Preston AM, Gurisik E, Bartley C, Laybutt DR, Biden TJ (2009). "Reduced endoplasmic reticulum (ER)-to-Golgi protein trafficking contributes to ER stress in lipotoxic mouse beta cells by promoting protein overload". Diabetologia. 52 (11): 2369–2373. doi:10.1007/s00125-009-1506-5. PMID 19727664.
^Cunha DA, Hekerman P, Ladrière L, Bazarra-Castro A, Ortis F, Wakeham MC, et al. (2008). "Initiation and execution of lipotoxic ER stress in pancreatic beta-cells". Journal of Cell Science. 121 (14): 2308–2318. doi:10.1242/jcs.026062. PMC3675788. PMID 18559892.
^Oyadomari S, Takeda K, Takiguchi M, Gotoh T, Matsumoto M, Wada I, Akira S, Araki E, Mori M (2001). "Nitric oxide-induced apoptosis in pancreatic beta cells is mediated by the endoplasmic reticulum stress pathway". Proceedings of the National Academy of Sciences of the United States of America. 98 (19): 10845–10850. doi:10.1073/pnas.191207498. PMC58562. PMID 11526215.
^ abcHotamisligil, Gökhan S. (March 2010). "Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease". Cell. 140 (6): 900–917. doi:10.1016/j.cell.2010.02.034. ISSN 0092-8674. PMC2887297. PMID 20303879.
^Pirot P, Eizirik DL, Cardozo AK (2006). "Interferon-gamma potentiates endoplasmic reticulum stress-induced death by reducing pancreatic beta cell defence mechanisms". Diabetologia. 49 (6): 1229–1236. doi:10.1007/s00125-006-0214-7. PMID 16604358.
^ abWang, Miao; Kaufman, Randal J. (January 2016). "Protein misfolding in the endoplasmic reticulum as a conduit to human disease". Nature. 529 (7586): 326–335. Bibcode:2016Natur.529..326W. doi:10.1038/nature17041. ISSN 0028-0836. PMID 26791723. S2CID 4446276.
^Hu, Hai; Tian, Mingxing; Ding, Chan; Yu, Shengqing (2019-01-04). "The C/EBP Homologous Protein (CHOP) Transcription Factor Functions in Endoplasmic Reticulum Stress-Induced Apoptosis and Microbial Infection". Frontiers in Immunology. 9: 3083. doi:10.3389/fimmu.2018.03083. ISSN 1664-3224. PMC6328441. PMID 30662442.
^van Schadewijk, Annemarie; van’t Wout, Emily F. A.; Stolk, Jan; Hiemstra, Pieter S. (March 2012). "A quantitative method for detection of spliced X-box binding protein-1 (XBP1) mRNA as a measure of endoplasmic reticulum (ER) stress". Cell Stress and Chaperones. 17 (2): 275–279. doi:10.1007/s12192-011-0306-2. ISSN 1355-8145. PMC3273559. PMID 22038282.
April 09, 2024
endoplasmic, reticulum, stress, beta, cells, beta, cells, heavily, engaged, synthesis, secretion, insulin, they, therefore, particularly, sensitive, endoplasmic, reticulum, stress, subsequent, unfolded, protein, response, severe, prolonged, episodes, stress, l. Beta cells are heavily engaged in the synthesis and secretion of insulin They are therefore particularly sensitive to endoplasmic reticulum ER stress and the subsequent unfolded protein response UPR Severe or prolonged episodes of ER stress can lead to the death of beta cells 1 which can contribute to the development of both type I and type II diabetes 2 ER stress in beta cells links obesity to type 2 diabetes and inflammation to type 1 diabetes ER stress in peripheral cells has also been linked to insulin resistance 3 a precursor to type 2 diabetes Contents 1 Activation of ER stress 2 ER stress and inflammation 3 Resolution of ER stress 4 Measurement 5 ReferencesActivation of ER stress edit nbsp A model of how ER stress is involved in b cell death and type II diabetes mellitusER stress can be activated by a variety of factors In experimental conditions excessive lipid which can happen following obesity a common condition preceding type 2 diabetes and pro inflammatory cytokines which can occur following an inflammation a common cause for type 1 diabetes can activate ER stress in beta cells Causes such as defective protein processing 4 and trafficking 5 or inappropriate calcium regulation 6 are likely in lipid mediated ER stress On the other hand cytokines are likely to activate ER stress by decreasing the calcium pump Serca2b also known as Atp2a2 leading to subsequent depletion in ER calcium stores 7 ER stress and inflammation editAll three of the pathways involved in the resolution of ER stress by the unfolded protein response UPR are also related to inflammation 8 The two pathways are very connected and both have been shown to activate each other 8 Resolution of ER stress editActivation of ER stress by lipids results in a typical unfolded protein response UPR to primarily restore ER function whereas cytokine activated ER stress leads to an atypical UPR that preferentially activate apoptosis in beta cells 9 The UPR is activated when GRP78 a k a BiP a protein folding chaperone is recruited to assist in protein folding In b cells insulin production is a major source of improperly folded protein 1 GRP78 is normally bound to the luminal domain of ATF6 IRE1 and PERK which prevents them from initiating their respective pathways of the UPR When GRP78 is recruited to assist in protein folding unbound ATF6 IRE1 and PERK are able to initiate the UPR 10 The UPR is also activated by cytokines 8 ER stress activates apoptosis through C EBP homologous protein CHOP 11 Measurement editER stress can be measured using quantitative real time RT PCR to measure the rate at which XBP1 is cleaved by IRE1 when the UPR is activated 12 XBP1 mRNA cleavage leads to the translation of a transcription factor for genes that resolve ER stress 10 Measuring the rate at which XBP1 is cleaved gives a quantitative measure of ER stress in real time References edit a b Eizirik DL Cardozo AK Cnop M 2008 The role for endoplasmic reticulum stress in diabetes mellitus Endocrine Reviews 29 1 42 61 doi 10 1210 er 2007 0015 PMID 18048764 Laybutt DR Preston AM Akerfeldt MC Kench JG Busch AK Biankin AV Biden TJ 2007 Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes Diabetologia 50 4 752 763 doi 10 1007 s00125 006 0590 z PMID 17268797 Wellen Kathryn E Hotamisligil Gokhan S 2005 05 02 Inflammation stress and diabetes Journal of Clinical Investigation 115 5 1111 1119 doi 10 1172 JCI25102 ISSN 0021 9738 PMC 1087185 PMID 15864338 Jeffrey KD Alejandro EU Luciani DS Kalynyak TB Hu X Li H Lin Y Townsend RR Polonsky KS Johnson JD 2008 Carboxypeptidase E mediates palmitate induced beta cell ER stress and apoptosis Proceedings of the National Academy of Sciences of the United States of America 105 24 8452 8457 doi 10 1073 pnas 0711232105 PMC 2448857 PMID 18550819 Preston AM Gurisik E Bartley C Laybutt DR Biden TJ 2009 Reduced endoplasmic reticulum ER to Golgi protein trafficking contributes to ER stress in lipotoxic mouse beta cells by promoting protein overload Diabetologia 52 11 2369 2373 doi 10 1007 s00125 009 1506 5 PMID 19727664 Cunha DA Hekerman P Ladriere L Bazarra Castro A Ortis F Wakeham MC et al 2008 Initiation and execution of lipotoxic ER stress in pancreatic beta cells Journal of Cell Science 121 14 2308 2318 doi 10 1242 jcs 026062 PMC 3675788 PMID 18559892 Oyadomari S Takeda K Takiguchi M Gotoh T Matsumoto M Wada I Akira S Araki E Mori M 2001 Nitric oxide induced apoptosis in pancreatic beta cells is mediated by the endoplasmic reticulum stress pathway Proceedings of the National Academy of Sciences of the United States of America 98 19 10845 10850 doi 10 1073 pnas 191207498 PMC 58562 PMID 11526215 a b c Hotamisligil Gokhan S March 2010 Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease Cell 140 6 900 917 doi 10 1016 j cell 2010 02 034 ISSN 0092 8674 PMC 2887297 PMID 20303879 Pirot P Eizirik DL Cardozo AK 2006 Interferon gamma potentiates endoplasmic reticulum stress induced death by reducing pancreatic beta cell defence mechanisms Diabetologia 49 6 1229 1236 doi 10 1007 s00125 006 0214 7 PMID 16604358 a b Wang Miao Kaufman Randal J January 2016 Protein misfolding in the endoplasmic reticulum as a conduit to human disease Nature 529 7586 326 335 Bibcode 2016Natur 529 326W doi 10 1038 nature17041 ISSN 0028 0836 PMID 26791723 S2CID 4446276 Hu Hai Tian Mingxing Ding Chan Yu Shengqing 2019 01 04 The C EBP Homologous Protein CHOP Transcription Factor Functions in Endoplasmic Reticulum Stress Induced Apoptosis and Microbial Infection Frontiers in Immunology 9 3083 doi 10 3389 fimmu 2018 03083 ISSN 1664 3224 PMC 6328441 PMID 30662442 van Schadewijk Annemarie van t Wout Emily F A Stolk Jan Hiemstra Pieter S March 2012 A quantitative method for detection of spliced X box binding protein 1 XBP1 mRNA as a measure of endoplasmic reticulum ER stress Cell Stress and Chaperones 17 2 275 279 doi 10 1007 s12192 011 0306 2 ISSN 1355 8145 PMC 3273559 PMID 22038282 Retrieved from https en wikipedia org w index php title Endoplasmic reticulum stress in beta cells amp oldid 1189363493, wikipedia, wiki, book, books, library,
