Ormdl3 regulation of specific ceramides is dispensable for β-cell function and glucose homeostasis under obesogenic conditions.
Ormdl3 regulation of specific ceramides is dispensable for β-cell function and glucose homeostasis under obesogenic conditions.
复制标题
特定神经酰胺的 Ormdl3 调节对于肥胖条件下的 β 细胞功能和葡萄糖稳态是可有可无的。
DOI：
10.1101/2023.02.11.528130
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Engin,Feyza
中科院分区：
文献类型：
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作者：
Hurley,LiamD;Lee,Hugo;Wade,Gina;Simcox,Judith;Engin,Feyza
神经鞘脂的慢性升高导致β细胞衰竭。ORMDL3已被确定为神经鞘脂稳态的关键调节因子，然而，其在胰腺β细胞病理生理中的功能尚不清楚。在这里，我们在胰腺β-细胞中建立了缺乏Ormdl3的小鼠模型（Ormdl3β - / -）。我们发现β细胞ormd3的缺失不会改变标准鼠粮中葡萄糖耐量、胰岛素敏感性、胰岛素分泌、胰岛形态或细胞神经酰胺水平。虽然Ormdl3β - / -小鼠在代谢参数或胰岛结构方面没有表现出任何改变，但脂质组学分析显示，它们的胰岛中超长链神经酰胺的水平显著升高。综上所述，我们的研究结果表明，Ormdl3的缺失并不足以影响β细胞功能或全身葡萄糖和胰岛素的稳态，但Ormdl3的缺失确实会改变特定的鞘脂水平。
Chronic elevation of sphingolipids contributes to β-cell failure. ORMDL3 has been identified as a key regulator of sphingolipid homeostasis, however, its function in pancreatic β-cell pathophysiology remains unclear. Here, we generated a mouse model lacking Ormdl3 within pancreatic β-cells (Ormdl3β−/−). We show that loss of β-cell Ormdl3 does not alter glucose tolerance, insulin sensitivity, insulin secretion, islet morphology, or cellular ceramide levels on standard chow diet. When challenged with a high fat diet, while Ormdl3β−/− mice did not exhibit any alteration in metabolic parameters or islet architecture, lipidomics analysis revealed significantly higher levels of very long chain ceramides in their islets. Taken together, our results reveal that loss of Ormdl3 alone is not sufficient to impinge upon β-cell function or whole-body glucose and insulin homeostasis, but loss of Ormdl3 does alter specific sphingolipid levels.