<scp>ORMDL</scp>3 and its implication in inflammatory disorders

Ma, Xiaochun; Long, Feng; Yun, Yan; Deng, Jiehui; Wei, Shijun; Zhang, Qian; Li, Jinzhang; Zhang, Haizhou; Zhang, Wenlong; Wang, Zhengjun; Liu, Qiji

doi:10.1111/1756-185x.13324

Cited by 9 publications

(13 citation statements)

References 55 publications

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“…Incidence of inflammatory bowel disease also increases with overweight and obesity [ 32 ]. Previous studies have suggested that mammalian ORMDL3 contributes to the regulation of inflammation through multiple pathways, including endoplasmic reticulum stress, autophagy, apoptosis, and B lymphocyte fate determination [ 11 , 15 , 33 ]. Our results showed that genetic loss of Ormdl3 in mice could exacerbate the overall obesity phenotypes by blocking the development of beige fat and thermogenesis of brown/beige fat.…”

Section: Discussionmentioning

confidence: 99%

Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation

Song

Zan

Qin

et al. 2022

Molecular Metabolism

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Objective Genome-wide association studies identified ORMDL3 as an obesity-related gene, and its expression was negatively correlated with body mass index. However, the precise biological roles of ORMDL3 in obesity and lipid metabolism remain uncharacterized. Here, we investigate the function of ORMDL3 in adipose tissue thermogenesis and high fat diet (HFD)-induced insulin resistance. Methods Ormdl3 -deficient ( Ormdl3 −/− ) mice were employed to delineate the function of ORMDL3 in brown adipose tissue (BAT) thermogenesis and white adipose tissue (WAT) browning. Glucose and lipid homeostasis in Ormdl3 −/− mice fed a HFD were assessed. The lipid composition in adipose tissue was evaluated by mass spectrometry. Primary adipocytes in culture were used to determine the mechanism by which ORMDL3 regulates white adipose browning. Results BAT thermogenesis and WAT browning were significantly impaired in Ormdl3 −/− mice upon cold exposure or administration with the β3 adrenergic agonist. In addition, compared to WT mice, Ormdl3 −/− mice displayed increased weight gain and insulin resistance in response to HFD. The induction of uncoupling protein 1 (UCP1), a marker of thermogenesis, was attenuated in primary adipocytes derived from Ormdl3 −/− mice. Importantly, ceramide levels were elevated in the adipose tissue of Ormdl3 −/− mice. In addition, the reduction in thermogenesis and increase in body weight caused by Ormdl3 deficiency could be rescued by inhibiting the production of ceramides. Conclusion Our findings suggest that ORMDL3 contributes to the regulation of BAT thermogenesis, WAT browning, and insulin resistance.

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Section: Discussionmentioning

confidence: 99%

Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation

Song

Zan

Qin

et al. 2022

Molecular Metabolism

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“…In macrophages, the anomalous expression of ORMDL3 affects autophagy and contributes to the risk of inflammatory diseases (21). Autophagy is a process that determines a cells fate in different ways (36); it can be regulated by any of the three branches of the UPR (ATF6, IRE1a, and PERK), although regulation is cell-specific and context-specific (12,(15)(16)(17)(18). Interestingly, it is reported that autophagy plays a crucial role in mast cell degranulation.…”

Section: Discussionmentioning

confidence: 99%

“…However, the regulatory role of mammals ORMDL proteins in lipid metabolism appears to be much more complicated. Kiefer and his colleagues demonstrated that mammalian SPT activity seems to be affected only when simultaneously enhancing the expression of ORMDL1, 2, and 3 while solo manipulation of any member had no effect (11)(12)(13). As an endoplasmic reticulum (ER)-resident transmembrane protein, ORMDL3 also regulates ER stress (ERS) and unfolded protein response (UPR) (10,14).…”

Section: Introductionmentioning

confidence: 99%

“…Multiple studies have attempted to uncover the physiological role of ORMDL3 in the cells involved in allergic asthma including airway epithelial cells, eosinophils, macrophages and B cells (8,9,20,21). ORMDL3 specifically binds to and inhibits the sarcoendoplasmic reticulum calcium ATPase (SERCA) 2b resulting in reduction of ER Ca 2+ concentration and activation of ERS-induced UPR signaling in HEK293 cells (12,22). Conversely, ORMDL3 has been shown to increase ATF6a level and subsequent induction of SERCA2b expression in human bronchial epithelial cells (BEC) (8), suggesting ORMDL3 mediated ERS-UPR response is cell-specific.…”

Section: Introductionmentioning

confidence: 99%

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ORMDL3 Functions as a Negative Regulator of Antigen-Mediated Mast Cell Activation via an ATF6-UPR-Autophagy–Dependent Pathway

Ullah

Jin

et al. 2021

Front. Immunol.

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Antigen (Ag)-mediated mast cell activation plays a critical role in the immunopathology of IgE-dependent allergic diseases. Restraining the signaling cascade that regulates the release of mast cell-derived inflammatory mediators is an attractive therapeutic strategy to treat allergic diseases. Orosomucoid-like-3 (ORMDL3) regulates the endoplasmic reticulum stress (ERS)-induced unfolded protein response (UPR) and autophagy. Although ERS/UPR/autophagy pathway is crucial in Ag-induced mast cell activation, it is unknown whether ORMDL3 regulates the ERS/UPR/autophagy pathway during mast cell activation. In this study, we found that ORMDL3 expression was downregulated in Ag-activated MC/9 cells. Overexpression of ORMDL3 significantly inhibited degranulation, and cytokine/chemokine production, while the opposite effect was observed with ORMDL3 knockdown in MC/9 cells. Importantly, ORMDL3 overexpression upregulated mediators of ERS-UPR (SERCA2b, ATF6) and autophagy (Beclin 1 and LC3BII). Knockdown of ATF6 and/or inhibition of autophagy reversed the decreased degranulation and cytokine/chemokine expression caused by ORMDL3 overexpression. Moreover, in vivo knockdown of ORMDL3 and/or ATF6 enhanced passive cutaneous anaphylaxis (PCA) reactions in mouse ears. These data indicate that ORMDL3 suppresses Ag-mediated mast cell activation via an ATF6 UPR-autophagy dependent pathway and thus, attenuates anaphylactic reaction. This highlights a potential mechanism to intervene in mast cell mediated diseases.

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“…57 After further screening, ER-related genes closely related to the development of UC are identified, including orosmucoid-like 3 (ORMDL3), anterior gradient 2 (AGR2), and X-box binding protein-1 (XBP1). [58][59][60] Orosmucoid-like 3 can promote UPR by altering ER-mediated Ca 2+ homeostasis, which may be a cause of UC. 58,61 The gene mutation testing is performed on UC patients, and it has been found that AGR2 is downregulated in UC patients compared with normal controls.…”

Section: Apoptosis and Er Stressmentioning

confidence: 99%

Excessive Apoptosis in Ulcerative Colitis: Crosstalk Between Apoptosis, ROS, ER Stress, and Intestinal Homeostasis

Wan

Yang

Jiang

et al. 2021

Inflammatory Bowel Diseases

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Ulcerative colitis (UC), an etiologically complicated and relapsing gastrointestinal disease, is characterized by the damage of mucosal epithelium and destruction of the intestinal homeostasis, which has caused a huge social and economic burden on the health system all over the world. Its pathogenesis is multifactorial, including environmental factors, genetic susceptibility, epithelial barrier defect, symbiotic flora imbalance, and dysregulated immune response. Thus far, although immune cells have become the focus of most research, it is increasingly clear that intestinal epithelial cells play an important role in the pathogenesis and progression of UC. Notably, apoptosis is a vital catabolic process in cells, which is crucial to maintain the stability of intestinal environment and regulate intestinal ecology. In this review, the mechanism of apoptosis induced by reactive oxygen species and endoplasmic reticulum stress, as well as excessive apoptosis in intestinal epithelial dysfunction and gut microbiology imbalance are systematically and comprehensively summarized. Further understanding the role of apoptosis in the pathogenesis of UC may provide a novel strategy for its therapy in clinical practices and the development of new drugs.

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ORMDL3 and its implication in inflammatory disorders

Cited by 9 publications

References 55 publications

Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation

Ablation of ORMDL3 impairs adipose tissue thermogenesis and insulin sensitivity by increasing ceramide generation

ORMDL3 Functions as a Negative Regulator of Antigen-Mediated Mast Cell Activation via an ATF6-UPR-Autophagy–Dependent Pathway

Excessive Apoptosis in Ulcerative Colitis: Crosstalk Between Apoptosis, ROS, ER Stress, and Intestinal Homeostasis

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