ParkinsonCanadaV1, PascalFrancis, Corpus, bibRecord, 000218

Ubiquitin C-terminal hydrolase L1 is required for pancreatic beta cell survival and function in lipotoxic conditions

Identifieur interne : 000218 ( PascalFrancis/Corpus ); précédent : 000217; suivant : 000219

Ubiquitin C-terminal hydrolase L1 is required for pancreatic beta cell survival and function in lipotoxic conditions

Auteurs : K. Y. Chu ; H. Li ; K. Wada ; J. D. Johnson

Source :

Diabetologia : (Berlin) [ 0012-186X ] ; 2012.

RBID : Pascal:12-0133521

Descripteurs français

Pascal (Inist)
- Ubiquitine, Hydrolases, Cellule β, Survie, Apoptose, Maladie de Parkinson, Diabète de type 2.

English descriptors

KwdEn :
- Apoptosis, Hydrolases, Parkinson disease, Survival, Type 2 diabetes, Ubiquitin, β Cell.

Abstract

Aims/hypothesis Ubiquitin C-terminal hydrolase L1 (UCHL1) is associated with neurodegenerative diseases and has been suggested to have roles in pancreatic beta cells. Our proteomic analysis revealed that UCHL 1 was the most increased protein in MIN6 cells exposed to palmitate. The present study used a genetic loss-of-function model to test the hypothesis that UCHL1 is required for normal beta cell function and fate under lipotoxic conditions. Methods Human islets, mouse islets and MIN6 cells were used to analyse UCHL1 protein levels and regulation of UCHL1 by palmitate. The levels of free mono-ubiquitin and poly-ubiquitinated proteins were assessed. Gracile axonal dystrophy (GAD) mutant mice lacking UCHL1 were fed a normal or lipotoxic high-fat diet. Glucose tolerance, insulin tolerance and insulin secretion were assessed in vivo. Beta cell death and proliferation were assessed by TUNEL and proliferating cell nuclear antigen (PCNA) staining. Insulin secretion, calcium signalling, endoplasmic reticulum (ER) stress, apoptosis and SNARE protein levels were assessed in vitro. Results UCHL1 protein, which was highly specific to beta cells, was increased by palmitate at basal glucose, but not in the context of hyperglycaemia associated with frank diabetes. Although islet development and function were initially normal in Uchl1^-/- mice, a 4-week high-fat diet caused glucose intolerance and impaired insulin secretion. Uchl1^-/- mice had increased ER stress and beta cell apoptosis. The levels of SNARE proteins were dysregulated in Uchl1^-/- islets. Palmitate-stimulated vesicle-associated membrane protein 2 (VAMP2) ubiquitination was modulated by a chemical UCHL1 inhibitor. Conclusions/interpretation Together, these data suggest that UCHL1 has essential functional and anti-apoptotic roles in beta cells under stress conditions associated with lipotoxicity.

Notice en format standard (ISO 2709)

Pour connaître la documentation sur le format Inist Standard.

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C01	`01`		`ENG`	@0 Aims/hypothesis Ubiquitin C-terminal hydrolase L1 (UCHL1) is associated with neurodegenerative diseases and has been suggested to have roles in pancreatic beta cells. Our proteomic analysis revealed that UCHL 1 was the most increased protein in MIN6 cells exposed to palmitate. The present study used a genetic loss-of-function model to test the hypothesis that UCHL1 is required for normal beta cell function and fate under lipotoxic conditions. Methods Human islets, mouse islets and MIN6 cells were used to analyse UCHL1 protein levels and regulation of UCHL1 by palmitate. The levels of free mono-ubiquitin and poly-ubiquitinated proteins were assessed. Gracile axonal dystrophy (GAD) mutant mice lacking UCHL1 were fed a normal or lipotoxic high-fat diet. Glucose tolerance, insulin tolerance and insulin secretion were assessed in vivo. Beta cell death and proliferation were assessed by TUNEL and proliferating cell nuclear antigen (PCNA) staining. Insulin secretion, calcium signalling, endoplasmic reticulum (ER) stress, apoptosis and SNARE protein levels were assessed in vitro. Results UCHL1 protein, which was highly specific to beta cells, was increased by palmitate at basal glucose, but not in the context of hyperglycaemia associated with frank diabetes. Although islet development and function were initially normal in Uchl1^-/- mice, a 4-week high-fat diet caused glucose intolerance and impaired insulin secretion. Uchl1^-/- mice had increased ER stress and beta cell apoptosis. The levels of SNARE proteins were dysregulated in Uchl1^-/- islets. Palmitate-stimulated vesicle-associated membrane protein 2 (VAMP2) ubiquitination was modulated by a chemical UCHL1 inhibitor. Conclusions/interpretation Together, these data suggest that UCHL1 has essential functional and anti-apoptotic roles in beta cells under stress conditions associated with lipotoxicity.
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Format Inist (serveur)

NO :	PASCAL 12-0133521 INIST
ET :	Ubiquitin C-terminal hydrolase L1 is required for pancreatic beta cell survival and function in lipotoxic conditions
AU :	CHU (K. Y.); LI (H.); WADA (K.); JOHNSON (J. D.)
AF :	Laboratory of Molecular Signaling in Diabetes, Diabetes Research Group, Department of Cellular and Physiological Sciences, University of British Columbia, 5358 Life Sciences Building, 2350 Health Sciences Mall/Vancouver, BC V6T 1Z3/Canada (1 aut., 2 aut., 4 aut.); Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry Kodaira/Tokyo/Japon (3 aut.)
DT :	Publication en série; Niveau analytique
SO :	Diabetologia : (Berlin); ISSN 0012-186X; Allemagne; Da. 2012; Vol. 55; No. 1; Pp. 128-140; Bibl. 51 ref.
LA :	Anglais
EA :	Aims/hypothesis Ubiquitin C-terminal hydrolase L1 (UCHL1) is associated with neurodegenerative diseases and has been suggested to have roles in pancreatic beta cells. Our proteomic analysis revealed that UCHL 1 was the most increased protein in MIN6 cells exposed to palmitate. The present study used a genetic loss-of-function model to test the hypothesis that UCHL1 is required for normal beta cell function and fate under lipotoxic conditions. Methods Human islets, mouse islets and MIN6 cells were used to analyse UCHL1 protein levels and regulation of UCHL1 by palmitate. The levels of free mono-ubiquitin and poly-ubiquitinated proteins were assessed. Gracile axonal dystrophy (GAD) mutant mice lacking UCHL1 were fed a normal or lipotoxic high-fat diet. Glucose tolerance, insulin tolerance and insulin secretion were assessed in vivo. Beta cell death and proliferation were assessed by TUNEL and proliferating cell nuclear antigen (PCNA) staining. Insulin secretion, calcium signalling, endoplasmic reticulum (ER) stress, apoptosis and SNARE protein levels were assessed in vitro. Results UCHL1 protein, which was highly specific to beta cells, was increased by palmitate at basal glucose, but not in the context of hyperglycaemia associated with frank diabetes. Although islet development and function were initially normal in Uchl1^-/- mice, a 4-week high-fat diet caused glucose intolerance and impaired insulin secretion. Uchl1^-/- mice had increased ER stress and beta cell apoptosis. The levels of SNARE proteins were dysregulated in Uchl1^-/- islets. Palmitate-stimulated vesicle-associated membrane protein 2 (VAMP2) ubiquitination was modulated by a chemical UCHL1 inhibitor. Conclusions/interpretation Together, these data suggest that UCHL1 has essential functional and anti-apoptotic roles in beta cells under stress conditions associated with lipotoxicity.
CC :	002B21E01A; 002B17G; 002B17A01
FD :	Ubiquitine; Hydrolases; Cellule β; Survie; Apoptose; Maladie de Parkinson; Diabète de type 2
FG :	Enzyme; Pancréas endocrine; Ilot Langerhans; Mort cellulaire; Maladie dégénérative; Pathologie du système nerveux; Pathologie de l'encéphale; Syndrome extrapyramidal; Pathologie du système nerveux central; Endocrinopathie; Maladie métabolique
ED :	Ubiquitin; Hydrolases; β Cell; Survival; Apoptosis; Parkinson disease; Type 2 diabetes
EG :	Enzyme; Endocrine pancreas; Langerhans islet; Cell death; Degenerative disease; Nervous system diseases; Cerebral disorder; Extrapyramidal syndrome; Central nervous system disease; Endocrinopathy; Metabolic diseases
SD :	Ubiquitina; Hydrolases; Célula β; Sobrevivencia; Apoptosis; Parkinson enfermedad; Diabetes de tipo 2
LO :	INIST-13012.354000508429220200
ID :	12-0133521

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Pascal:12-0133521

Le document en format XML

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<front><div type="abstract" xml:lang="en">Aims/hypothesis Ubiquitin C-terminal hydrolase L1 (UCHL1) is associated with neurodegenerative diseases and has been suggested to have roles in pancreatic beta cells. Our proteomic analysis revealed that UCHL 1 was the most increased protein in MIN6 cells exposed to palmitate. The present study used a genetic loss-of-function model to test the hypothesis that UCHL1 is required for normal beta cell function and fate under lipotoxic conditions. Methods Human islets, mouse islets and MIN6 cells were used to analyse UCHL1 protein levels and regulation of UCHL1 by palmitate. The levels of free mono-ubiquitin and poly-ubiquitinated proteins were assessed. Gracile axonal dystrophy (GAD) mutant mice lacking UCHL1 were fed a normal or lipotoxic high-fat diet. Glucose tolerance, insulin tolerance and insulin secretion were assessed in vivo. Beta cell death and proliferation were assessed by TUNEL and proliferating cell nuclear antigen (PCNA) staining. Insulin secretion, calcium signalling, endoplasmic reticulum (ER) stress, apoptosis and SNARE protein levels were assessed in vitro. Results UCHL1 protein, which was highly specific to beta cells, was increased by palmitate at basal glucose, but not in the context of hyperglycaemia associated with frank diabetes. Although islet development and function were initially normal in Uchl1<sup>-/-</sup>
 mice, a 4-week high-fat diet caused glucose intolerance and impaired insulin secretion. Uchl1<sup>-/-</sup>
 mice had increased ER stress and beta cell apoptosis. The levels of SNARE proteins were dysregulated in Uchl1<sup>-/-</sup>
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<fC01 i1="01" l="ENG"><s0>Aims/hypothesis Ubiquitin C-terminal hydrolase L1 (UCHL1) is associated with neurodegenerative diseases and has been suggested to have roles in pancreatic beta cells. Our proteomic analysis revealed that UCHL 1 was the most increased protein in MIN6 cells exposed to palmitate. The present study used a genetic loss-of-function model to test the hypothesis that UCHL1 is required for normal beta cell function and fate under lipotoxic conditions. Methods Human islets, mouse islets and MIN6 cells were used to analyse UCHL1 protein levels and regulation of UCHL1 by palmitate. The levels of free mono-ubiquitin and poly-ubiquitinated proteins were assessed. Gracile axonal dystrophy (GAD) mutant mice lacking UCHL1 were fed a normal or lipotoxic high-fat diet. Glucose tolerance, insulin tolerance and insulin secretion were assessed in vivo. Beta cell death and proliferation were assessed by TUNEL and proliferating cell nuclear antigen (PCNA) staining. Insulin secretion, calcium signalling, endoplasmic reticulum (ER) stress, apoptosis and SNARE protein levels were assessed in vitro. Results UCHL1 protein, which was highly specific to beta cells, was increased by palmitate at basal glucose, but not in the context of hyperglycaemia associated with frank diabetes. Although islet development and function were initially normal in Uchl1<sup>-/-</sup>
 mice, a 4-week high-fat diet caused glucose intolerance and impaired insulin secretion. Uchl1<sup>-/-</sup>
 mice had increased ER stress and beta cell apoptosis. The levels of SNARE proteins were dysregulated in Uchl1<sup>-/-</sup>
 islets. Palmitate-stimulated vesicle-associated membrane protein 2 (VAMP2) ubiquitination was modulated by a chemical UCHL1 inhibitor. Conclusions/interpretation Together, these data suggest that UCHL1 has essential functional and anti-apoptotic roles in beta cells under stress conditions associated with lipotoxicity.</s0>
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<s5>01</s5>
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<s5>21</s5>
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<s5>22</s5>
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<s5>26</s5>
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<s5>27</s5>
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<s5>27</s5>
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<fC07 i1="09" i2="X" l="SPA"><s0>Sistema nervosio central patología</s0>
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<s5>28</s5>
</fC07>
<fC07 i1="10" i2="X" l="ENG"><s0>Endocrinopathy</s0>
<s5>28</s5>
</fC07>
<fC07 i1="10" i2="X" l="SPA"><s0>Endocrinopatía</s0>
<s5>28</s5>
</fC07>
<fC07 i1="11" i2="X" l="FRE"><s0>Maladie métabolique</s0>
<s5>29</s5>
</fC07>
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<s5>29</s5>
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<fC07 i1="11" i2="X" l="SPA"><s0>Metabolismo patología</s0>
<s5>29</s5>
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<server><NO>PASCAL 12-0133521 INIST</NO>
<ET>Ubiquitin C-terminal hydrolase L1 is required for pancreatic beta cell survival and function in lipotoxic conditions</ET>
<AU>CHU (K. Y.); LI (H.); WADA (K.); JOHNSON (J. D.)</AU>
<AF>Laboratory of Molecular Signaling in Diabetes, Diabetes Research Group, Department of Cellular and Physiological Sciences, University of British Columbia, 5358 Life Sciences Building, 2350 Health Sciences Mall/Vancouver, BC V6T 1Z3/Canada (1 aut., 2 aut., 4 aut.); Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry Kodaira/Tokyo/Japon (3 aut.)</AF>
<DT>Publication en série; Niveau analytique</DT>
<SO>Diabetologia : (Berlin); ISSN 0012-186X; Allemagne; Da. 2012; Vol. 55; No. 1; Pp. 128-140; Bibl. 51 ref.</SO>
<LA>Anglais</LA>
<EA>Aims/hypothesis Ubiquitin C-terminal hydrolase L1 (UCHL1) is associated with neurodegenerative diseases and has been suggested to have roles in pancreatic beta cells. Our proteomic analysis revealed that UCHL 1 was the most increased protein in MIN6 cells exposed to palmitate. The present study used a genetic loss-of-function model to test the hypothesis that UCHL1 is required for normal beta cell function and fate under lipotoxic conditions. Methods Human islets, mouse islets and MIN6 cells were used to analyse UCHL1 protein levels and regulation of UCHL1 by palmitate. The levels of free mono-ubiquitin and poly-ubiquitinated proteins were assessed. Gracile axonal dystrophy (GAD) mutant mice lacking UCHL1 were fed a normal or lipotoxic high-fat diet. Glucose tolerance, insulin tolerance and insulin secretion were assessed in vivo. Beta cell death and proliferation were assessed by TUNEL and proliferating cell nuclear antigen (PCNA) staining. Insulin secretion, calcium signalling, endoplasmic reticulum (ER) stress, apoptosis and SNARE protein levels were assessed in vitro. Results UCHL1 protein, which was highly specific to beta cells, was increased by palmitate at basal glucose, but not in the context of hyperglycaemia associated with frank diabetes. Although islet development and function were initially normal in Uchl1<sup>-/-</sup>
 mice, a 4-week high-fat diet caused glucose intolerance and impaired insulin secretion. Uchl1<sup>-/-</sup>
 mice had increased ER stress and beta cell apoptosis. The levels of SNARE proteins were dysregulated in Uchl1<sup>-/-</sup>
 islets. Palmitate-stimulated vesicle-associated membrane protein 2 (VAMP2) ubiquitination was modulated by a chemical UCHL1 inhibitor. Conclusions/interpretation Together, these data suggest that UCHL1 has essential functional and anti-apoptotic roles in beta cells under stress conditions associated with lipotoxicity.</EA>
<CC>002B21E01A; 002B17G; 002B17A01</CC>
<FD>Ubiquitine; Hydrolases; Cellule β; Survie; Apoptose; Maladie de Parkinson; Diabète de type 2</FD>
<FG>Enzyme; Pancréas endocrine; Ilot Langerhans; Mort cellulaire; Maladie dégénérative; Pathologie du système nerveux; Pathologie de l'encéphale; Syndrome extrapyramidal; Pathologie du   système nerveux central; Endocrinopathie; Maladie métabolique</FG>
<ED>Ubiquitin; Hydrolases; β Cell; Survival; Apoptosis; Parkinson disease; Type 2 diabetes</ED>
<EG>Enzyme; Endocrine pancreas; Langerhans islet; Cell death; Degenerative disease; Nervous system diseases; Cerebral disorder; Extrapyramidal syndrome; Central nervous system disease; Endocrinopathy; Metabolic diseases</EG>
<SD>Ubiquitina; Hydrolases; Célula β; Sobrevivencia; Apoptosis; Parkinson enfermedad; Diabetes de tipo 2</SD>
<LO>INIST-13012.354000508429220200</LO>
<ID>12-0133521</ID>
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Ubiquitin C-terminal hydrolase L1 is required for pancreatic beta cell survival and function in lipotoxic conditions

Ubiquitin C-terminal hydrolase L1 is required for pancreatic beta cell survival and function in lipotoxic conditions

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