Differential Expression of Ormdl Genes in the Islets of Mice and Humans with Obesity

Lee, Hugo; Fenske, Rachel J.; Akcan, Tuğçe; Domask, Elliot; Davis, Dawn Belt; Kimple, Michelle E.; Engin, Feyza

doi:10.1016/j.isci.2020.101324

Cited by 12 publications

(16 citation statements)

References 62 publications

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“…This serum recognizes all members of the ORMDL family at least of murine, human, and rat origin. The quality of this serum in recognizing changes in the expression of ORMDL family members was confirmed elsewhere ( 32 ).…”

Section: Methodssupporting

confidence: 59%

ORMDL2 Deficiency Potentiates the ORMDL3-Dependent Changes in Mast Cell Signaling

et al. 2021

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The systemic anaphylactic reaction is a life-threatening allergic response initiated by activated mast cells. Sphingolipids are an essential player in the development and attenuation of this response. De novo synthesis of sphingolipids in mammalian cells is inhibited by the family of three ORMDL proteins (ORMDL1, 2, and 3). However, the cell and tissue-specific functions of ORMDL proteins in mast cell signaling are poorly understood. This study aimed to determine cross-talk of ORMDL2 and ORMDL3 proteins in IgE-mediated responses. To this end, we prepared mice with whole-body knockout (KO) of Ormdl2 and/or Ormdl3 genes and studied their role in mast cell-dependent activation events in vitro and in vivo. We found that the absence of ORMDL3 in bone marrow-derived mast cells (BMMCs) increased the levels of cellular sphingolipids. Such an increase was further raised by simultaneous ORMDL2 deficiency, which alone had no effect on sphingolipid levels. Cells with double ORMDL2 and ORMDL3 KO exhibited increased intracellular levels of sphingosine-1-phosphate (S1P). Furthermore, we found that concurrent ORMDL2 and ORMDL3 deficiency increased IκB-α phosphorylation, degranulation, and production of IL-4, IL-6, and TNF-α cytokines in antigen-activated mast cells. Interestingly, the chemotaxis towards antigen was increased in all mutant cell types analyzed. Experiments in vivo showed that passive cutaneous anaphylaxis (PCA), which is initiated by mast cell activation, was increased only in ORMDL2,3 double KO mice, supporting our in vitro observations with mast cells. On the other hand, ORMDL3 KO and ORMDL2,3 double KO mice showed faster recovery from passive systemic anaphylaxis, which could be mediated by increased levels of blood S1P presented in such mice. Our findings demonstrate that Ormdl2 deficiency potentiates the ORMDL3-dependent changes in mast cell signaling.

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Section: Methodssupporting

confidence: 59%

ORMDL2 Deficiency Potentiates the ORMDL3-Dependent Changes in Mast Cell Signaling

et al. 2021

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“…Some of the differentially regulated proteins identified in RyR2 KO and IRBIT KO cells are dysregulated in diabetes and/or play a key role in β-cell function. Among these are PCSK1 45 and ORMDL1/2 (sphingolipid biosynthesis regulator 1/2) 46 which are reduced in both RyR2 KO and IRBIT KO cells, Abat (GABA aminotransferase) 47 , and Kcnj11 (Kir6.2) 48 which are reduced in RyR2 KO cells. The Ca 2+ -dependent adhesion molecule Cdh2 (N-cadhedrin) is also reduced in both RyR2 KO and IRBIT KO cells.…”

Section: Discussionmentioning

confidence: 99%

RyR2/IRBIT regulates insulin gene transcript, insulin content, and secretion in the insulinoma cell line INS-1

Harvey

LaVigne

Dar

et al. 2022

Sci Rep

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The role of ER Ca2+ release via ryanodine receptors (RyR) in pancreatic β-cell function is not well defined. Deletion of RyR2 from the rat insulinoma INS-1 (RyR2KO) enhanced IP3 receptor activity stimulated by 7.5 mM glucose, coincident with reduced levels of the protein IP3Receptor Binding protein released with Inositol 1,4,5 Trisphosphate (IRBIT). Insulin content, basal (2.5 mM glucose) and 7.5 mM glucose-stimulated insulin secretion were reduced in RyR2KO and IRBITKO cells compared to controls. INS2 mRNA levels were reduced in both RyR2KO and IRBITKO cells, but INS1 mRNA levels were specifically decreased in RyR2KO cells. Nuclear localization of S-adenosylhomocysteinase (AHCY) was increased in RyR2KO and IRBITKO cells. DNA methylation of the INS1 and INS2 gene promotor regions was very low, and not different among RyR2KO, IRBITKO, and controls, but exon 2 of the INS1 and INS2 genes was more extensively methylated in RyR2KO and IRBITKO cells. Exploratory proteomic analysis revealed that deletion of RyR2 or IRBIT resulted in differential regulation of 314 and 137 proteins, respectively, with 41 in common. These results suggest that RyR2 regulates IRBIT levels and activity in INS-1 cells, and together maintain insulin content and secretion, and regulate the proteome, perhaps via DNA methylation.

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“…Some of the differentially regulated proteins identified in RyR2 KO and IRBIT KO cells are dysregulated in diabetes and/or play a key role in β-cell function. Among these are PCSK1 [43] and ORMDL1/2 (sphingolipid biosynthesis regulator 1/2) [44] which are reduced in both RyR2 KO and IRBIT KO cells, and IAPP (islet amyloid polypeptide), Acyl (ATP-citrate lyase), and Abat (GABA aminotransferase) [45], and Kcnj11 (Kir6.2) [46] which are reduced in RyR2 KO cells. The Ca 2+ -dependent adhesion molecule Cdh2 (N-cadhedrin) is also reduced in both RyR2 KO and IRBIT KO cells.…”

Section: Discussionmentioning

confidence: 99%

RyR2/IRBIT regulates insulin gene transcription, insulin content, and secretion in the insulinoma cell line INS-1

Harvey

LaVigne²,

Dar³

et al. 2021

Preprint

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The role of ER Ca2+ release via ryanodine receptors (RyR) in pancreatic β-cell function is not well defined. Deletion of RyR2 from the rat insulinoma INS-1 (RyR2KO) enhanced the Ca2+ integral (AUC) stimulated by 7.5 mM glucose, and rendered it sensitive to block by the IP3 receptor inhibitor xestospongin C, coincident with reduced levels of the protein IP3Receptor Binding protein released with Inositol 1,4,5 Trisphosphate (IRBIT; aka AHCYL1). Deletion of IRBIT from INS-1 cells (IRBITKO) increased the Ca2+ AUC in response to 7.5 mM glucose and induced xestospongin sensitivity. Insulin content and basal (2.5 mM glucose) and 7.5 mM glucose-stimulated insulin secretion were reduced in RyR2KO cells and more modestly reduced in IRBITKO cells compared to controls. INS2 mRNA levels were reduced in both RyR2KO and IRBITKO cells, but INS1 mRNA levels were specifically decreased in RyR2KO cells. Nuclear localization of S-adenosylhomocysteinase (AHCY) was increased in RyR2KO and IRBITKO cells. DNA methylation of the INS1 and INS2 gene promotor regions was very low, and not different among RyR2KO, IRBITKO, and controls. In contrast, exon 2 of the INS1 and INS2 genes was more extensively methylated in RyR2KO and IRBITKO cells than in controls. Proteomics analysis using LC-MS/MS revealed that deletion of RyR2 or IRBIT resulted in differential regulation of 314 and 137 proteins, respectively, with 41 in common. These results suggest that RyR2 regulates IRBIT levels and activity in INS-1 cells, and together maintain insulin content and secretion, and regulate the proteome, perhaps via DNA methylation.One sentence SummaryDeletion of RyR2 from INS-1 cells had the unanticipated effect of reducing IRBIT proteins levels, and both RyR2 and IRBIT contribute to maintenance of glucose- stimulated insulin secretion.

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Differential Expression of Ormdl Genes in the Islets of Mice and Humans with Obesity

Cited by 12 publications

References 62 publications

ORMDL2 Deficiency Potentiates the ORMDL3-Dependent Changes in Mast Cell Signaling

ORMDL2 Deficiency Potentiates the ORMDL3-Dependent Changes in Mast Cell Signaling

RyR2/IRBIT regulates insulin gene transcript, insulin content, and secretion in the insulinoma cell line INS-1

RyR2/IRBIT regulates insulin gene transcription, insulin content, and secretion in the insulinoma cell line INS-1

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