Transcriptional Activation of the Proglucagon Gene by Lithium and β-Catenin in Intestinal Endocrine L Cells

Abstract

The proglucagon gene encodes several peptide hormones that regulate blood glucose homeostasis, growth of the small intestine, and satiety. Among them, glucagon-like peptide 1 (GLP-1) lowers blood glucose levels in patients with diabetes and inhibits eating and drinking in fasted rats. Although proglucagon transcription and GLP-1 synthesis were shown to be activated by forskolin and other protein kinase A (PKA) activators, deleting or mutating the cAMP-response element (CRE) only moderately attenuates the proglucagon gene promoter in response to PKA activation. Therefore, PKA may activate proglucagon transcription via a mechanism independent of the CRE motif. Recently, PKA was shown to phosphorylate and inactivate GSK-3␤, a key mediator in the Wnt signaling pathway. We show here that lithium, an inhibitor of GSK-3␤, activates proglucagon gene transcription and stimulates GLP-1 synthesis in an intestinal endocrine L cell line, GLUTag. The activation was also observed in primary fetal rat intestinal cell (FRIC) cultures, but not in a pancreatic A cell line. Co-transfection of ␤-catenin, a downstream effector of GSK-3␤ activities, activated the proglucagon gene promoter without a CRE. Furthermore, forskolin and 8-Br-cAMP phosphorylated GSK-3␤ at serine 9 in intestinal proglucagon-producing cells, and both lithium and forskolin induced the accumulation of free ␤-catenin in these cell lines. These observations indicate that the proglucagon gene is among the targets of the Wnt signaling pathway.

Regulation of insulin secretion, glucokinase gene transcription and beta cell proliferation by adipocyte-derived Wnt signalling molecules

“…In addition, Wnt signalling molecules and Frizzled receptors are expressed in the endocrine pancreas of both mice and humans [12,16,33] and regulate insulin secretion [17] and beta cell proliferation [19]. In contrast, the canonical Wnt signalling pathway cannot be activated in glucagon-producing alpha cells [34,35]. We investigated canonical (i.e.…”

Regulation of Proglucagon Transcription by Activated Transcription Factor (ATF) 3 and a Novel Isoform, ATF3b, through the cAMP-response Element/ATF Site of the Proglucagon Gene Promoter

“…Intriguingly, regulation of proglucagon gene expression by the Wnt signaling pathway has recently been demonstrated in enteroendocrine L cells. However, regulation of proglucagon gene expression by lithium via this pathway has not been shown in pancreatic ␣ cells (27).…”

PPARβ/δ Activation Induces Enteroendocrine L Cell GLP-1 Production

“…Since previous reports have demonstrated that GLP-1 receptor agonists inhibit β-cell apoptosis under conditions of glucolipotoxicity 46,47 and that PPARβ/δ activation also prevents palmitate-induced β-cell apoptosis 28 , we speculated that the protective effect of PPARβ/δ on β- Further, it has been established that lithium, a GSK-3β inhibitor, and insulin increase proglucagon expression through stimulation of the β-catenin-TCF/Lef signaling pathway only in enteroendocrine GLP-1-producting L cells, but not in pancreatic glucagon-producing α-cells 26,27 . This is due to the fact that the transcription factor TCF-4 is expressed in small intestine epithelium 39 , but not in islet α-cells 27 …”

“…Moreover, insulin and GSK-3β inhibitors, such as lithium, stimulate G2 response element activity specifically in enteroendocrine L cells through the β-catenin/TCF-4 signaling pathway resulting in increased GLP-1 production 26,27 .…”