microRNA-483 Protects Pancreatic β-Cells by Targeting ALDH1A3

Wang, Zhihong; Mohan, Ramkumar; Chen, Xinqian; Matson, Katy; Waugh, Jackson; Mao, Yiping; Zhang, Shungang; Li, Wanzhen; Tang, Xiaohu; Satin, Leslie S.; Tang, Xiaoqing

doi:10.1210/endocr/bqab031

Cited by 17 publications

(14 citation statements)

References 50 publications

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“…In contrast, overexpression of miR-7 in murine pancreatic islets leads to loss of β-cell identity by suppressing β-cell function-associated gene expression, including a significant decrease in β-cell transcription factors, as well as in insulin synthesis [95]. In a recent study, miR-483 deletion in mice resulted in β-cell dedifferentiation, as indicated by elevated expression of aldehyde dehydrogenase family 1, subfamily A3 (Aldh1a3), a marker of β-cell dedifferentiation [96].…”

Section: Micrornas (Mirnas) and Long Non-coding Rnas (Lncrnas)mentioning

confidence: 99%

A Brief Review of the Mechanisms of β-Cell Dedifferentiation in Type 2 Diabetes

Khin

Lee

2021

Nutrients

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Diabetes is a metabolic disease characterized by hyperglycemia. Over 90% of patients with diabetes have type 2 diabetes. Pancreatic β-cells are endocrine cells that produce and secrete insulin, an essential endocrine hormone that regulates blood glucose levels. Deficits in β-cell function and mass play key roles in the onset and progression of type 2 diabetes. Apoptosis has been considered as the main contributor of β-cell dysfunction and decrease in β-cell mass for a long time. However, recent studies suggest that β-cell failure occurs mainly due to increased β-cell dedifferentiation rather than limited β-cell proliferation or increased β-cell death. In this review, we summarize the current advances in the understanding of the pancreatic β-cell dedifferentiation process including potential mechanisms. A better understanding of β-cell dedifferentiation process will help to identify novel therapeutic targets to prevent and/or reverse β-cell loss in type 2 diabetes.

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Section: Micrornas (Mirnas) and Long Non-coding Rnas (Lncrnas)mentioning

confidence: 99%

A Brief Review of the Mechanisms of β-Cell Dedifferentiation in Type 2 Diabetes

Khin

Lee

2021

Nutrients

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“…Body weight and blood glucose level were measured weekly. Mice were fasted for 6 h and fasting blood glucose was measured from tail vein blood with an Accuchek glucometer (Abbott Diabetes Care) as described 23 . For plasma hormone assay, blood was harvested from orbital venous sinus of fasted mice and measured by Ultrasensitive insulin ELISA kit and glucagon ELISA kit, respectively (Crystal Chem).…”

Section: Methodsmentioning

confidence: 99%

“…Pancreas was dissected, fixed in 4% freshly prepared paraformaldehyde (pH 7.4) for 24 h at 4 °C, and then processed routinely for paraffin embedding 23 . For miRNA in-situ hybridization, sections were first deparaffinized and rehydrated, then treated with Proteinase K (Roch, 40 µg/ml) as described 25 .…”

Section: Methodsmentioning

confidence: 99%

“…In contrast, mice with miR-375 deletion exhibit hyperglycemia due to decreased β-cell and increased α-cell mass and function 22 . MiR-483 deletion induces β-cell dedifferentiation in mice fed high-fat diet by elevating Aldh1a3, a dedifferentiation marker 23 . However, the physiological importance of individual miRNAs in regulating glucose homeostasis and diabetes pathogenesis remain largely unclear due to mild phenotypic effects in most of miRNA knockouts.…”

Section: Introductionmentioning

confidence: 99%

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Transgenic overexpression of microRNA-30d in pancreatic beta-cells progressively regulates beta-cell function and identity

Mao

Schoenborn

Wang

et al. 2022

Sci Rep

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Abnormal microRNA functions are closely associated with pancreatic β-cell loss and dysfunction in type 2 diabetes. Dysregulation of miR-30d has been reported in the individuals with diabetes. To study how miR-30d affects pancreatic β-cell functions, we generated two transgenic mouse lines that specifically overexpressed miR-30d in β-cells at distinct low and high levels. Transgenic overexpressed miR-30d systemically affected β-cell function. Elevated miR-30d at low-level (TgL, 2-fold) had mild effects on signaling pathways and displayed no significant changes to metabolic homeostasis. In contrast, transgenic mice with high-level of miR-30d expression (TgH, 12-fold) exhibited significant diet-induced hyperglycemia and β-cell dysfunction. In addition, loss of β-cell identity was invariably accompanied with increased insulin/glucagon-double positive bihormonal cells and excess plasma glucagon levels. The transcriptomic analysis revealed that miR-30d overexpression inhibited β-cell-enriched gene expression and induced α-cell-enriched gene expression. These findings implicate that an appropriate miR-30d level is essential in maintaining normal β-cell identity and function.

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“…Most of the published studies regarding Mir483 are related to cancer, with the majority of the reports classifying MIR483 (human nomenclature 14 ) as an onco-miR 17,18 , though some studies provide evidence for an onco-suppressor action in certain contexts 19,20 . Mir483 has been associated with a number of biological processes, such as cellular differentiation 21 , proliferation 22 , survival 23 , melatonin synthesis 24 , insulin production 25,26 , and vascular homeostasis 27 . Importantly, Mir483 has been shown to be regulated by environmental cues such as diet 28 and temperature 29 .…”

Section: Mainmentioning

confidence: 99%

The imprinted Mir483 is a growth suppressor and metabolic regulator functioning through IGF1

Sandovici

Fernandez‐Twinn

Campbell

et al. 2022

Preprint

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Mir483 is a conserved and highly expressed microRNA in placental mammals, embedded within the Igf2 gene. Here, we uncover the control mechanisms and physiological functions of Mir483 in vivo, by generating constitutive loss-of-function and over-expressing mice. Mir483 expression is imprinted and dependent on the Igf2 promoters and Igf2/H19 imprinting control region. Over-expression of Mir483 causes severe mid-gestation fetal, but not placental, growth restriction, and late lethality. Fetal death is prevented by restoring Mir483 to endogenous levels using an inducible transgenic system. Continuous postnatal Mir483 over-expression induces growth stunting, elevated hepatic lipid content, increased adiposity, reduced local and systemic IGF1 levels and increased GH. The growth phenotypes are rescued by IGF1 infusion. Our findings provide evidence for a novel functional antagonism between a growth-suppressor microRNA and its growth-promoter host gene, and suggest that Mir483 evolved to limit excessive tissue growth through repression of IGF ligand signalling.

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microRNA-483 Protects Pancreatic β-Cells by Targeting ALDH1A3

Cited by 17 publications

References 50 publications

A Brief Review of the Mechanisms of β-Cell Dedifferentiation in Type 2 Diabetes

A Brief Review of the Mechanisms of β-Cell Dedifferentiation in Type 2 Diabetes

Transgenic overexpression of microRNA-30d in pancreatic beta-cells progressively regulates beta-cell function and identity

The imprinted Mir483 is a growth suppressor and metabolic regulator functioning through IGF1

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