Hypoxia-inducible factor-1α mediates the expression of mature β cell-disallowed genes in hypoxia-induced β cell dedifferentiation

Liu, Na; Cai, Xiangheng; Liu, Tengli; Zou, Jiaqi; Wang, Le; Wang, Guanqiao; Liu, Yaojuan; Ding, Xuejie; Zhang, Boya; Sun, Peng; Liang, Rui; Wang, Shusen

doi:10.1016/j.bbrc.2019.12.063

Cited by 14 publications

(9 citation statements)

References 23 publications

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“…Notably, hypoxia-inducible factor-1α (HIF-1α) was identified as a key regulator of hypoxia-induced de-differentiation of β cells by upregulating mature β cell-disallowed genes including LDHA [ 259 ], discussed later in more detail. ERRα and ERRγ are regarded as key players of metabolic control [ 260 ].…”

Section: Mex Mir Signaling and Functional Immaturity Of β Cellsmentioning

confidence: 99%

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Milk Exosomal microRNAs: Postnatal Promoters of β Cell Proliferation but Potential Inducers of β Cell De-Differentiation in Adult Life

Melnik

Schmitz

2022

IJMS

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Pancreatic β cell expansion and functional maturation during the birth-to-weaning period is driven by epigenetic programs primarily triggered by growth factors, hormones, and nutrients provided by human milk. As shown recently, exosomes derived from various origins interact with β cells. This review elucidates the potential role of milk-derived exosomes (MEX) and their microRNAs (miRs) on pancreatic β cell programming during the postnatal period of lactation as well as during continuous cow milk exposure of adult humans to bovine MEX. Mechanistic evidence suggests that MEX miRs stimulate mTORC1/c-MYC-dependent postnatal β cell proliferation and glycolysis, but attenuate β cell differentiation, mitochondrial function, and insulin synthesis and secretion. MEX miR content is negatively affected by maternal obesity, gestational diabetes, psychological stress, caesarean delivery, and is completely absent in infant formula. Weaning-related disappearance of MEX miRs may be the critical event switching β cells from proliferation to TGF-β/AMPK-mediated cell differentiation, whereas continued exposure of adult humans to bovine MEX miRs via intake of pasteurized cow milk may reverse β cell differentiation, promoting β cell de-differentiation. Whereas MEX miR signaling supports postnatal β cell proliferation (diabetes prevention), persistent bovine MEX exposure after the lactation period may de-differentiate β cells back to the postnatal phenotype (diabetes induction).

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Section: Mex Mir Signaling and Functional Immaturity Of β Cellsmentioning

confidence: 99%

“…Intriguingly, HIF1AN , the gene encoding FIH-1, is a predicted target gene of miR-148a [ 296 ]. Thus, MEX miR-148a may enhance HIF-1α-induced β cell glycolysis, which correlates with β cell de-differentiation and upregulation of disallowed genes [ 259 ].…”

Section: Mex Mir Signaling and Functional Immaturity Of β Cellsmentioning

confidence: 99%

Milk Exosomal microRNAs: Postnatal Promoters of β Cell Proliferation but Potential Inducers of β Cell De-Differentiation in Adult Life

Melnik

Schmitz

2022

IJMS

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“…Mechanistically, dedifferentiation is controlled by several transcription factors. For instance, hypoxia-inducible factor-1α (HIF-1α) has been shown to facilitate dedifferentiation of β-cells (Liu et al, 2020). Conditional knockout of FOXO1 TF resulted in dedifferentiation of β-cells and has been shown to be the major cause of β-cell failure in Type II diabetes (Talchai C 2012).…”

Section: Discussionmentioning

confidence: 99%

Deubiquitinase USP1 influences the dedifferentiation of mouse pancreatic β-cells

Francis

Sheshadri

Prasanna

et al. 2022

Preprint

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Diabetes is a metabolic disease caused majorly due to loss of insulin secreting β-cells. Along with apoptosis, recent reports revealed dedifferentiation to be the added reason for the reduced β-cell mass. The Ubiquitin Proteasome system comprising of E3 ligase and deubiquitinases (DUBs) control several key aspects of pancreatic β-cell functions. The role of deubiquitinases in orchestrating the dedifferentiation process in several cancers have been well deciphered, but its role in dedifferentiation of pancreatic β-cells remains elusive. In this study, screening for key DUBs that regulate dedifferentiation, identified USP1 to be specifically involved in the process. Inhibition of USP1 either by genetic intervention or small molecule inhibitor ML323 restored epithelial phenotype of β-cells, but not with inhibition of other DUBs. Conversely overexpression of USP1 was sufficient to dedifferentiate β-cells, even in absence of dedifferentiation inducing cues. Mechanistic insight showed USP1 to probably mediate its effect via modulating the expression of Inhibitor of Differentiation (ID) 2. Further, in an in vivo streptozotocin (STZ) induced dedifferentiation mouse model system, treatment with ML323 rescued the hyperglycaemic state. Overall, this study assigns a novel role to USP1 in dedifferentiation of β-cells and its inhibition may have a therapeutic application of reducing the β-cell loss during diabetes.

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“…An increase in expression of GLUT1, several glycolytic enzymes, LDH-A and pyruvate dehydrogenase kinase (PDK1) and a parallel decrease in mitochondrial oxygen consumption strengthens the ATP production through the glycolytic pathway [219]. HIF-1α was shown in a recent study to mediate expression of β-cell disallowed genes like Ldha/LDH-A, Glut1/GLUT1, a marker of dedifferentiation aldehyde dehydrogenase 1 family, member A3 (Aldh1a3/ALDH1A3/ALDH1A3) and endocrine progenitor cell marker NGN3 and to suppress the expression of β-cell functional genes like Glut2/GLUT2, Neurod1/NEUROD1, Mafa/MAFA, Nkx6.1 and Pdx1 suggesting that hypoxia-induced pathways are involved in β-cell dedifferentiation [220]. Long-term hypoxia in β-cells results in cell-death, typically by necrosis [221] and also induction of apoptosis-related pathways upon hypoxia exposure has been described in β-cells [222,223].…”

Section: β-Cell Dedifferentiation As the Adaptation To Metabolic And Redox Changesmentioning

confidence: 97%

Redox Homeostasis in Pancreatic β-Cells: From Development to Failure

2021

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Redox status is a key determinant in the fate of β-cell. These cells are not primarily detoxifying and thus do not possess extensive antioxidant defense machinery. However, they show a wide range of redox regulating proteins, such as peroxiredoxins, thioredoxins or thioredoxin reductases, etc., being functionally compartmentalized within the cells. They keep fragile redox homeostasis and serve as messengers and amplifiers of redox signaling. β-cells require proper redox signaling already in cell ontogenesis during the development of mature β-cells from their progenitors. We bring details about redox-regulated signaling pathways and transcription factors being essential for proper differentiation and maturation of functional β-cells and their proliferation and insulin expression/maturation. We briefly highlight the targets of redox signaling in the insulin secretory pathway and focus more on possible targets of extracellular redox signaling through secreted thioredoxin1 and thioredoxin reductase1. Tuned redox homeostasis can switch upon chronic pathological insults towards the dysfunction of β-cells and to glucose intolerance. These are characteristics of type 2 diabetes, which is often linked to chronic nutritional overload being nowadays a pandemic feature of lifestyle. Overcharged β-cell metabolism causes pressure on proteostasis in the endoplasmic reticulum, mainly due to increased demand on insulin synthesis, which establishes unfolded protein response and insulin misfolding along with excessive hydrogen peroxide production. This together with redox dysbalance in cytoplasm and mitochondria due to enhanced nutritional pressure impact β-cell redox homeostasis and establish prooxidative metabolism. This can further affect β-cell communication in pancreatic islets through gap junctions. In parallel, peripheral tissues losing insulin sensitivity and overall impairment of glucose tolerance and gut microbiota establish local proinflammatory signaling and later systemic metainflammation, i.e., low chronic inflammation prooxidative properties, which target β-cells leading to their dedifferentiation, dysfunction and eventually cell death.

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Hypoxia-inducible factor-1α mediates the expression of mature β cell-disallowed genes in hypoxia-induced β cell dedifferentiation

Cited by 14 publications

References 23 publications

Milk Exosomal microRNAs: Postnatal Promoters of β Cell Proliferation but Potential Inducers of β Cell De-Differentiation in Adult Life

Milk Exosomal microRNAs: Postnatal Promoters of β Cell Proliferation but Potential Inducers of β Cell De-Differentiation in Adult Life

Deubiquitinase USP1 influences the dedifferentiation of mouse pancreatic β-cells

Redox Homeostasis in Pancreatic β-Cells: From Development to Failure

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