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Artikel ; Online: Endoplasmic Reticulum Protein Quality Control in β Cells.

Shrestha, Neha / Reinert, Rachel B / Qi, Ling

Seminars in cell & developmental biology

2020 Band 103, Seite(n) 59–67

Abstract: Type 1 and type 2 diabetes are associated with loss of β cell function. Optimal β cell function is linked to protein homeostasis in the endoplasmic reticulum (ER). Here, we review the roles of ER protein quality-control mechanisms, including the unfolded ...

Abstract	Type 1 and type 2 diabetes are associated with loss of β cell function. Optimal β cell function is linked to protein homeostasis in the endoplasmic reticulum (ER). Here, we review the roles of ER protein quality-control mechanisms, including the unfolded protein response (UPR), autophagy (specifically ER-phagy) and ER-associated degradation (ERAD), in β cells. We propose that different quality control mechanisms may control different aspects of β cell biology (i.e. function, survival, and identity), thereby contributing to disease pathogenesis.
Mesh-Begriff(e)	Diabetes Mellitus/metabolism ; Endoplasmic Reticulum/metabolism ; Humans ; Insulin-Secreting Cells/metabolism ; Membrane Proteins/metabolism
Chemische Substanzen	Membrane Proteins
Sprache	Englisch
Erscheinungsdatum	2020-05-08
Erscheinungsland	England
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1312473-0
ISSN	1096-3634 ; 1084-9521
ISSN (online)	1096-3634
ISSN	1084-9521
DOI	10.1016/j.semcdb.2020.04.006
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Muscle-specific ER-associated degradation maintains postnatal muscle hypertrophy and systemic energy metabolism.

Abdon, Benedict / Liang, Yusheng / da Luz Scheffer, Débora / Torres, Mauricio / Shrestha, Neha / Reinert, Rachel B / Lu, You / Pederson, Brent / Bugarin-Lapuz, Amara / Kersten, Sander / Qi, Ling

JCI insight

2023 Band 8, Heft 17

Abstract: The growth of skeletal muscle relies on a delicate equilibrium between protein synthesis and degradation; however, how proteostasis is managed in the endoplasmic reticulum (ER) is largely unknown. Here, we report that the SEL1L-HRD1 ER-associated ... ...

Abstract	The growth of skeletal muscle relies on a delicate equilibrium between protein synthesis and degradation; however, how proteostasis is managed in the endoplasmic reticulum (ER) is largely unknown. Here, we report that the SEL1L-HRD1 ER-associated degradation (ERAD) complex, the primary molecular machinery that degrades misfolded proteins in the ER, is vital to maintain postnatal muscle growth and systemic energy balance. Myocyte-specific SEL1L deletion blunts the hypertrophic phase of muscle growth, resulting in a net zero gain of muscle mass during this developmental period and a 30% reduction in overall body growth. In addition, myocyte-specific SEL1L deletion triggered a systemic reprogramming of metabolism characterized by improved glucose sensitivity, enhanced beigeing of adipocytes, and resistance to diet-induced obesity. These effects were partially mediated by the upregulation of the myokine FGF21. These findings highlight the pivotal role of SEL1L-HRD1 ERAD activity in skeletal myocytes for postnatal muscle growth, and its physiological integration in maintaining whole-body energy balance.
Mesh-Begriff(e)	Humans ; Endoplasmic Reticulum-Associated Degradation ; Ubiquitin-Protein Ligases/metabolism ; Proteins/genetics ; Muscles/metabolism ; Energy Metabolism ; Hypertrophy/metabolism
Chemische Substanzen	Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Proteins ; SEL1L protein, human
Sprache	Englisch
Erscheinungsdatum	2023-08-03
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.170387
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Fibroblast Growth Factor 23-Induced Hypophosphatemia in Acute Leukemia.

Reinert, Rachel B / Bixby, Dale / Koenig, Ronald J

Journal of the Endocrine Society

2018 Band 2, Heft 5, Seite(n) 437–443

Abstract: Fibroblast growth factor 23 (FGF23)-induced hypophosphatemia is a rare paraneoplastic syndrome of phosphate wasting that, if unrecognized, may cause tumor-induced osteomalacia. It is classically associated with benign mesenchymal tumors but occasionally ... ...

Abstract	Fibroblast growth factor 23 (FGF23)-induced hypophosphatemia is a rare paraneoplastic syndrome of phosphate wasting that, if unrecognized, may cause tumor-induced osteomalacia. It is classically associated with benign mesenchymal tumors but occasionally has been found in patients with other malignancies. Hypophosphatemia has been associated with acute leukemia but has not previously been reported to be due to inappropriate FGF23 secretion. Here, we describe FGF23-induced severe hypophosphatemia and renal phosphate wasting associated with a mixed-phenotype Philadelphia chromosome-like acute leukemia in a previously healthy 22-year-old man. He was found to have low serum 1,25-dihydroxyvitamin D and extremely high FGF23 levels, as well as inappropriate urinary phosphorus excretion. The hypophosphatemia improved with calcitriol and oral phosphate treatment but normalized only during chemotherapy-induced ablation of the blasts. FGF23 levels declined with a reduction in peripheral blast counts. Using real-time reverse transcription polymerase chain reaction, we found that the leukemia cells were the source of FGF23. To our knowledge, this is the first description of FGF23-induced hypophosphatemia associated with acute leukemia. We recommend that the FGF23 paraneoplastic syndrome be considered as a possible etiology of hypophosphatemia in patients with acute leukemia.
Sprache	Englisch
Erscheinungsdatum	2018-04-06
Erscheinungsland	United States
Dokumenttyp	Case Reports
ISSN	2472-1972
ISSN (online)	2472-1972
DOI	10.1210/js.2018-00010
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Integration of ER protein quality control mechanisms defines β cell function and ER architecture.

Shrestha, Neha / Torres, Mauricio / Zhang, Jason / Lu, You / Haataja, Leena / Reinert, Rachel B / Knupp, Jeffrey / Chen, Yu-Jie / Parlakgul, Gunes / Arruda, Ana Paula / Tsai, Billy / Arvan, Peter / Qi, Ling

The Journal of clinical investigation

2023 Band 133, Heft 1

Abstract: Three principal ER quality-control mechanisms, namely, the unfolded protein response, ER-associated degradation (ERAD), and ER-phagy are each important for the maintenance of ER homeostasis, yet how they are integrated to regulate ER homeostasis and ... ...

Abstract	Three principal ER quality-control mechanisms, namely, the unfolded protein response, ER-associated degradation (ERAD), and ER-phagy are each important for the maintenance of ER homeostasis, yet how they are integrated to regulate ER homeostasis and organellar architecture in vivo is largely unclear. Here we report intricate crosstalk among the 3 pathways, centered around the SEL1L-HRD1 protein complex of ERAD, in the regulation of organellar organization in β cells. SEL1L-HRD1 ERAD deficiency in β cells triggers activation of autophagy, at least in part, via IRE1α (an endogenous ERAD substrate). In the absence of functional SEL1L-HRD1 ERAD, proinsulin is retained in the ER as high molecular weight conformers, which are subsequently cleared via ER-phagy. A combined loss of both SEL1L and autophagy in β cells leads to diabetes in mice shortly after weaning, with premature death by approximately 11 weeks of age, associated with marked ER retention of proinsulin and β cell loss. Using focused ion beam scanning electron microscopy powered by deep-learning automated image segmentation and 3D reconstruction, our data demonstrate a profound organellar restructuring with a massive expansion of ER volume and network in β cells lacking both SEL1L and autophagy. These data reveal at an unprecedented detail the intimate crosstalk among the 3 ER quality-control mechanisms in the dynamic regulation of organellar architecture and β cell function.
Mesh-Begriff(e)	Mice ; Animals ; Endoribonucleases/metabolism ; Endoplasmic Reticulum-Associated Degradation ; Proinsulin/genetics ; Proinsulin/metabolism ; Ubiquitin-Protein Ligases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Endoplasmic Reticulum/metabolism ; Proteins/metabolism
Chemische Substanzen	Endoribonucleases (EC 3.1.-) ; Proinsulin (9035-68-1) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Proteins
Sprache	Englisch
Erscheinungsdatum	2023-01-03
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI163584
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Integration of ER protein quality-control mechanisms defines β cell function and ER architecture

Neha Shrestha / Mauricio Torres / Jason Zhang / You Lu / Leena Haataja / Rachel B. Reinert / Jeffrey Knupp / Yu-Jie Chen / Allen H. Hunter / Gunes Parlakgul / Ana Paula Arruda / Billy Tsai / Peter Arvan / Ling Qi

The Journal of Clinical Investigation, Vol 133, Iss

2023 Band 1

Abstract	Three principal ER quality-control mechanisms, namely, the unfolded protein response, ER-associated degradation (ERAD), and ER-phagy are each important for the maintenance of ER homeostasis, yet how they are integrated to regulate ER homeostasis and organellar architecture in vivo is largely unclear. Here we report intricate crosstalk among the 3 pathways, centered around the SEL1L-HRD1 protein complex of ERAD, in the regulation of organellar organization in β cells. SEL1L-HRD1 ERAD deficiency in β cells triggers activation of autophagy, at least in part, via IRE1α (an endogenous ERAD substrate). In the absence of functional SEL1L-HRD1 ERAD, proinsulin is retained in the ER as high molecular weight conformers, which are subsequently cleared via ER-phagy. A combined loss of both SEL1L and autophagy in β cells leads to diabetes in mice shortly after weaning, with premature death by approximately 11 weeks of age, associated with marked ER retention of proinsulin and β cell loss. Using focused ion beam scanning electron microscopy powered by deep-learning automated image segmentation and 3D reconstruction, our data demonstrate a profound organellar restructuring with a massive expansion of ER volume and network in β cells lacking both SEL1L and autophagy. These data reveal at an unprecedented detail the intimate crosstalk among the 3 ER quality-control mechanisms in the dynamic regulation of organellar architecture and β cell function.
Schlagwörter	Cell biology ; Metabolism ; Medicine ; R
Thema/Rubrik (Code)	571
Sprache	Englisch
Erscheinungsdatum	2023-02-01T00:00:00Z
Verlag	American Society for Clinical Investigation
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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Artikel ; Online: Muscle-specific ER-associated degradation maintains postnatal muscle hypertrophy and systemic energy metabolism

Benedict Abdon / Yusheng Liang / Débora da Luz Scheffer / Mauricio Torres / Neha Shrestha / Rachel B. Reinert / You Lu / Brent Pederson / Amara Bugarin-Lapuz / Sander Kersten / Ling Qi

JCI Insight, Vol 8, Iss

2023 Band 17

Abstract	The growth of skeletal muscle relies on a delicate equilibrium between protein synthesis and degradation; however, how proteostasis is managed in the endoplasmic reticulum (ER) is largely unknown. Here, we report that the SEL1L-HRD1 ER-associated degradation (ERAD) complex, the primary molecular machinery that degrades misfolded proteins in the ER, is vital to maintain postnatal muscle growth and systemic energy balance. Myocyte-specific SEL1L deletion blunts the hypertrophic phase of muscle growth, resulting in a net zero gain of muscle mass during this developmental period and a 30% reduction in overall body growth. In addition, myocyte-specific SEL1L deletion triggered a systemic reprogramming of metabolism characterized by improved glucose sensitivity, enhanced beigeing of adipocytes, and resistance to diet-induced obesity. These effects were partially mediated by the upregulation of the myokine FGF21. These findings highlight the pivotal role of SEL1L-HRD1 ERAD activity in skeletal myocytes for postnatal muscle growth, and its physiological integration in maintaining whole-body energy balance.
Schlagwörter	Cell biology ; Muscle biology ; Medicine ; R
Thema/Rubrik (Code)	610
Sprache	Englisch
Erscheinungsdatum	2023-09-01T00:00:00Z
Verlag	American Society for Clinical investigation
Dokumenttyp	Artikel ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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Artikel: A Novel Receivership Model for Transition of Young Adults With Diabetes: Experience From a Single-center Academic Transition Program.

Iyengar, Jennifer J / Ang, Lynn / Rodeman, Kathryn Bux / Rao, Amith / Lin, Yu Kuei / Broome, David T / Fanous, Nada / Reinert, Rachel B / Konigsberg, Anna / Weatherup, Emily / Hagar, Christine / Rogosch, Danielle / Florek, Jacinta / Carey, Brittany / Wyckoff, Jennifer / Lee, Joyce / Thomas, Inas H / Soleimanpour, Scott A

Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists

2023 Band 30, Heft 2, Seite(n) 113–121

Abstract: Objective: The transition from pediatric to adult care for young adults with diabetes represents an important but often challenging time characterized by a shift from a family-centered care model of pediatrics to a patient-centered care model of adult ... ...

Abstract	Objective: The transition from pediatric to adult care for young adults with diabetes represents an important but often challenging time characterized by a shift from a family-centered care model of pediatrics to a patient-centered care model of adult medicine. We developed a structured transition program based on an adult receivership model at a large academic medical center to improve care coordination and patient satisfaction with the transition process. Methods: From 2016 to 2020, we implemented a series of quality improvement efforts for young adults aged 18 to 23 years with diabetes by incorporating best practices from the American Diabetes Association guidelines on care for emerging adults. We measured transition orientation attendance, patient satisfaction, hemoglobin A1c (HbA1c) pre- and post-transfer, and care gaps to determine the impact of the program. Results: In this study, 307 individuals with type 1 diabetes and 16 individuals with type 2 diabetes were taken care of by the adult endocrinology department at the University of Michigan between January 1, 2016 and October 31, 2020. We observed high attendance rates (86% among internal transfers) and favorable patient satisfaction scores for the transition orientation session. Despite the glycemic challenges posed during the transition, HbA1c modestly yet significantly improved 1-year after transfer (-0.4%, P < .01). Conclusion: We successfully established and maintained a young adult diabetes transition program using a quality improvement approach. Future work will focus on reducing care gaps at the time of transfer, assessing long-term retention rates, and enhancing care coordination for patients referred from outside the health network.
Mesh-Begriff(e)	Humans ; Young Adult ; Child ; Glycated Hemoglobin ; Transition to Adult Care ; Diabetes Mellitus, Type 2/therapy ; Diabetes Mellitus, Type 1/therapy ; Patient Satisfaction
Chemische Substanzen	Glycated Hemoglobin
Sprache	Englisch
Erscheinungsdatum	2023-11-27
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	1473503-9
ISSN	1530-891X
ISSN	1530-891X
DOI	10.1016/j.eprac.2023.11.008
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Human pancreatic capillaries and nerve fibers persist in type 1 diabetes despite beta cell loss.

Richardson, Tiffany M / Saunders, Diane C / Haliyur, Rachana / Shrestha, Shristi / Cartailler, Jean-Philippe / Reinert, Rachel B / Petronglo, Jenna / Bottino, Rita / Aramandla, Radhika / Bradley, Amber M / Jenkins, Regina / Phillips, Sharon / Kang, Hakmook / Caicedo, Alejandro / Powers, Alvin C / Brissova, Marcela

American journal of physiology. Endocrinology and metabolism

2023 Band 324, Heft 3, Seite(n) E251–E267

Abstract: The autonomic nervous system regulates pancreatic function. Islet capillaries are essential for the extension of axonal projections into islets, and both of these structures are important for appropriate islet hormone secretion. Because beta cells ... ...

Abstract	The autonomic nervous system regulates pancreatic function. Islet capillaries are essential for the extension of axonal projections into islets, and both of these structures are important for appropriate islet hormone secretion. Because beta cells provide important paracrine cues for islet glucagon secretion and neurovascular development, we postulated that beta cell loss in type 1 diabetes (T1D) would lead to a decline in intraislet capillaries and reduction of islet innervation, possibly contributing to abnormal glucagon secretion. To define morphological characteristics of capillaries and nerve fibers in islets and acinar tissue compartments, we analyzed neurovascular assembly across the largest cohort of T1D and normal individuals studied thus far. Because innervation has been studied extensively in rodent models of T1D, we also compared the neurovascular architecture between mouse and human pancreas and assembled transcriptomic profiles of molecules guiding islet angiogenesis and neuronal development. We found striking interspecies differences in islet neurovascular assembly but relatively modest differences at transcriptome level, suggesting that posttranscriptional regulation may be involved in this process. To determine whether islet neurovascular arrangement is altered after beta cell loss in T1D, we compared pancreatic tissues from non-diabetic, recent-onset T1D (<10-yr duration), and longstanding T1D (>10-yr duration) donors. Recent-onset T1D showed greater islet and acinar capillary density compared to non-diabetic and longstanding T1D donors. Both recent-onset and longstanding T1D had greater islet nerve fiber density compared to non-diabetic donors. We did not detect changes in sympathetic axons in either T1D cohort. Additionally, nerve fibers overlapped with extracellular matrix (ECM), supporting its role in the formation and function of axonal processes. These results indicate that pancreatic capillaries and nerve fibers persist in T1D despite beta cell loss, suggesting that alpha cell secretory changes may be decoupled from neurovascular components.
Mesh-Begriff(e)	Humans ; Mice ; Animals ; Diabetes Mellitus, Type 1/metabolism ; Islets of Langerhans/metabolism ; Glucagon/metabolism ; Capillaries/metabolism ; Glucagon-Secreting Cells/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Nerve Fibers/metabolism
Chemische Substanzen	Glucagon (9007-92-5)
Sprache	Englisch
Erscheinungsdatum	2023-01-25
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	603841-4
ISSN	1522-1555 ; 0193-1849
ISSN (online)	1522-1555
ISSN	0193-1849
DOI	10.1152/ajpendo.00246.2022
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Sel1L-Hrd1 ER-associated degradation maintains β cell identity via TGF-β signaling.

Shrestha, Neha / Liu, Tongyu / Ji, Yewei / Reinert, Rachel B / Torres, Mauricio / Li, Xin / Zhang, Maria / Tang, Chih-Hang Anthony / Hu, Chih-Chi Andrew / Liu, Chengyang / Naji, Ali / Liu, Ming / Lin, Jiandie D / Kersten, Sander / Arvan, Peter / Qi, Ling

The Journal of clinical investigation

2020 Band 130, Heft 7, Seite(n) 3499–3510

Abstract: β Cell apoptosis and dedifferentiation are 2 hotly debated mechanisms underlying β cell loss in type 2 diabetes; however, the molecular drivers underlying such events remain largely unclear. Here, we performed a side-by-side comparison of mice carrying β ...

Abstract	β Cell apoptosis and dedifferentiation are 2 hotly debated mechanisms underlying β cell loss in type 2 diabetes; however, the molecular drivers underlying such events remain largely unclear. Here, we performed a side-by-side comparison of mice carrying β cell-specific deletion of ER-associated degradation (ERAD) and autophagy. We reported that, while autophagy was necessary for β cell survival, the highly conserved Sel1L-Hrd1 ERAD protein complex was required for the maintenance of β cell maturation and identity. Using single-cell RNA-Seq, we demonstrated that Sel1L deficiency was not associated with β cell loss, but rather loss of β cell identity. Sel1L-Hrd1 ERAD controlled β cell identity via TGF-β signaling, in part by mediating the degradation of TGF-β receptor 1. Inhibition of TGF-β signaling in Sel1L-deficient β cells augmented the expression of β cell maturation markers and increased the total insulin content. Our data revealed distinct pathogenic effects of 2 major proteolytic pathways in β cells, providing a framework for therapies targeting distinct mechanisms of protein quality control.
Mesh-Begriff(e)	Adult ; Aged ; Animals ; Cell Survival/genetics ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/pathology ; Endoplasmic Reticulum ; Female ; HEK293 Cells ; Humans ; Insulin-Secreting Cells/metabolism ; Insulin-Secreting Cells/pathology ; Intracellular Signaling Peptides and Proteins/genetics ; Intracellular Signaling Peptides and Proteins/metabolism ; Male ; Mice ; Mice, Transgenic ; Middle Aged ; Proteins/genetics ; Proteins/metabolism ; Proteolysis ; Receptor, Transforming Growth Factor-beta Type I/genetics ; Receptor, Transforming Growth Factor-beta Type I/metabolism ; Signal Transduction ; Transforming Growth Factor beta/genetics ; Transforming Growth Factor beta/metabolism ; Ubiquitin-Protein Ligases/genetics ; Ubiquitin-Protein Ligases/metabolism
Chemische Substanzen	Intracellular Signaling Peptides and Proteins ; Proteins ; SEL1L protein, human ; Sel1h protein, mouse ; Transforming Growth Factor beta ; SYVN1 protein, human (EC 2.3.2.27) ; Syvn1 protein, mouse (EC 2.3.2.27) ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Receptor, Transforming Growth Factor-beta Type I (EC 2.7.11.30) ; TGFBR1 protein, human (EC 2.7.11.30) ; Tgfbr1 protein, mouse (EC 2.7.11.30)
Sprache	Englisch
Erscheinungsdatum	2020-02-28
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI134874
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Buch ; Online: ER-associated degradation maintains postnatal muscle hypertophy and systemic energy metabolism

Abdon, Benedict / Liang, Yusheng / da Luz Scheffer, Débora / Torres, Mauricio / Shrestha, Neha / Reinert, Rachel / Lu, You / Pederson, Brent / Bugarin-Lapuz, Amara / Kersten, Sander / Qi, Ling

2023

Abstract: The growth of skeletal muscle relies on a delicate equilibrium between protein synthesis and degradation; however, how proteostasis is managed in the endoplasmic reticulum is largely unknown. Here, we report that the SEL1L-HRD1 endoplasmic reticulum (ER)- ...

Abstract	The growth of skeletal muscle relies on a delicate equilibrium between protein synthesis and degradation; however, how proteostasis is managed in the endoplasmic reticulum is largely unknown. Here, we report that the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) complex, the primary molecular machinery that degrades misfolded proteins in the ER, is vital to maintain postnatal muscle growth and systemic energy balance. Myocyte-specific SEL1L deletion blunts the hypertrophic phase of muscle growth, resulting in a net zero gain of muscle mass during this developmental period and significant reduction in overall body growth. In addition, myocyte-specific SEL1L deletion triggered a systemic reprogramming of metabolism characterized by improved glucose sensitivity, enhanced beiging of adipocytes, and resistance to diet induced obesity. These effects were partially mediated by the upregulation of the myokine FGF21. These findings highlight the pivotal role of SEL1L-HRD1 ERAD activity in skeletal myocytes for postnatal muscle growth, and its physiological integration in maintaining whole-body energy balance. Overall design: Gene expression was profiled in gastrocnemius muscle isolated from 8-week-old wildtype and muscle-specific Sel1L-deficient mice. The growth of skeletal muscle relies on a delicate equilibrium between protein synthesis and degradation; however, how proteostasis is managed in the endoplasmic reticulum is largely unknown. Here, we report that the SEL1L-HRD1 endoplasmic reticulum (ER)-associated degradation (ERAD) complex, the primary molecular machinery that degrades misfolded proteins in the ER, is vital to maintain postnatal muscle growth and systemic energy balance. Myocyte-specific SEL1L deletion blunts the hypertrophic phase of muscle growth, resulting in a net zero gain of muscle mass during this developmental period and significant reduction in overall body growth. In addition, myocyte-specific SEL1L deletion triggered a systemic reprogramming of metabolism characterized ...
Schlagwörter	Mus musculus
Thema/Rubrik (Code)	610
Verlag	Wageningen University & Research
Erscheinungsland	nl
Dokumenttyp	Buch ; Online
Datenquelle	BASE - Bielefeld Academic Search Engine (Lebenswissenschaftliche Auswahl)

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