Hepatokine Fetuin-A disrupts functional maturation of pancreatic β-cells
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ABSTRACT:
PROVIDER: PRJNA605432 | ENA |
REPOSITORIES: ENA
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Project description:Neonatal beta-cells undergo a maturation process to acquire glucose responsiveness. We hypothesize that in later life, a partial reversal of this maturation might promote beta-cell dysfunction. We previously ascertained that fetuin-A, a fetal glycoprotein downregulated at birth but increasingly secreted when fatty liver develops, inhibits insulin secretion. Here, we evaluate fetuin-A’s impact on beta-cell maturation. In vitro maturation of neonatal porcine islet cell clusters (NICCs) promoted expression of beta-cell markers and TGFBR/SMAD signaling. Fetuin-A reduced both functional and proliferative gene expression and SMAD phosphorylation. Consequently, fetuin-A impaired glucose- and forskolin-dependent secretion, and reduced adaptive beta-cell proliferation. In adult human islets, fetuin-A abolished glucose responsiveness, diminished SMAD phosphorylation and downregulated functional and proliferative genes. Our findings suggest that perinatal decline of fetuin-A relieves TGFBR signaling in neonatal beta-cells, thereby facilitating the onset of postnatal maturation. However, this program remains revocable during adulthood, since fatty liver-derived fetuin-A reverses beta-cells’ maturity, conferring them a neonatal-like phenotype and contributing to their failure.
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Project description:Glis3 is expressed in pancreatic beta and PP cells. To identify down stream target genes of Glis3, we performed microarray analysis using pancreas total RNAs from 1 week-old WT and Glis3KO2 mice. insulin and pancreatic polypeptide (Ppy) was significantly decreased together with several other β cell markers, Glut2 and MafA by microarray analysis. Immunohistochemistry, QRT-PCR, and transmission electron microscopy indicated that postnatal Glis3KO2 pancreas still contains a large population of β cells that express Pdx-1, Nkx6.1, and Isl-1; however, insulin production and secretory granules were greatly reduced in these cells. In addition, chromogranin A (ChgA) and Urocortin 3, which are associated with mature β cells, was dramatically decreased in Glis3KO2 pancreas. These observations suggest that Glis3 plays a critical role in the maturation of pancreatic β cell phenotype.
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Project description:Using a unique model of cultured human beta cell senescence we show that chromatin reorganization leads to activation of enhancers regulating functional maturation genes, concomitantly with acquisition of glucose-stimulated insulin secretion capacity. Interferon-response genes are elevated in senescent beta cells, but cytokine-encoding senescence-associated secretory phenotype (SASP) genes are not. Human beta cell senescence thus involves chromatin-driven upregulation of a functional maturation program and of interferon-stimulated genes, changes that could increase both insulin secretion and immune reactivity.
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Project description:Using a unique model of cultured human beta cell senescence we show that chromatin reorganization leads to activation of enhancers regulating functional maturation genes, concomitantly with acquisition of glucose-stimulated insulin secretion capacity. Interferon-response genes are elevated in senescent beta cells, but cytokine-encoding senescence-associated secretory phenotype (SASP) genes are not. Human beta cell senescence thus involves chromatin-driven upregulation of a functional maturation program and of interferon-stimulated genes, changes that could increase both insulin secretion and immune reactivity.
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Project description:Using a unique model of cultured human beta cell senescence we show that chromatin reorganization leads to activation of enhancers regulating functional maturation genes, concomitantly with acquisition of glucose-stimulated insulin secretion capacity. Interferon-response genes are elevated in senescent beta cells, but cytokine-encoding senescence-associated secretory phenotype (SASP) genes are not. Human beta cell senescence thus involves chromatin-driven upregulation of a functional maturation program and of interferon-stimulated genes, changes that could increase both insulin secretion and immune reactivity.
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