失调的FicD amppylation通过破坏胰腺内分泌稳态导致糖尿病的临床前模型。

IF 7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2025-03-10 DOI:10.1016/j.molmet.2025.102120

Amanda K. Casey , Nathan M. Stewart , Naqi Zaidi , Hillery F. Gray , Hazel A. Fields , Masahiro Sakurai , Carlos A. Pinzon-Arteaga , Bret M. Evers , Jun Wu , Kim Orth

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引用次数: 0

摘要

双功能酶FicD催化内质网伴侣蛋白BiP的氨酰基化和去氨酰基化，以调节内质网稳态和未折叠蛋白反应（UPR）。具有精氨酸-丝氨酸突变的人hFicD破坏了FicD去氨酰基化活性，导致严重的新生儿糖尿病。我们在小鼠中产生mFicDR371S突变，以创建新生儿糖尿病的临床前小鼠模型。我们观察到，在多个组织和糖尿病的标志性标志物（包括葡萄糖耐受不良和血清胰岛素水平降低）中，BiP AMPylation水平升高。虽然mFicDR371S小鼠的胰腺在出生时看起来正常，但成年mFicDR371S小鼠的胰岛组织紊乱，并随着年龄的增长而发展。mFicDR371S小鼠为研究UPR相关糖尿病提供了临床前小鼠模型，并证明了FicD对组织弹性的重要性。

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Pre-clinical model of dysregulated FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis

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Pre-clinical model of dysregulated FicD AMPylation causes diabetes by disrupting pancreatic endocrine homeostasis

The bi-functional enzyme FicD catalyzes AMPylation and deAMPylation of the endoplasmic reticulum chaperone BiP to modulate ER homeostasis and the unfolded protein response (UPR). Human hFicD with an arginine-to-serine mutation disrupts FicD deAMPylation activity resulting in severe neonatal diabetes. We generated the mFicD^R371S mutation in mice to create a pre-clinical murine model for neonatal diabetes. We observed elevated BiP AMPylation levels across multiple tissues and signature markers for diabetes including glucose intolerance and reduced serum insulin levels. While the pancreas of mFicD^R371S mice appeared normal at birth, adult mFicD^R371S mice displayed disturbed pancreatic islet organization that progressed with age. mFicD^R371S mice provide a preclinical mouse model for the study of UPR associated diabetes and demonstrate the essentiality of FicD for tissue resilience.

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.