| First Author | Girard R | Year | 2019 |
| Journal | Sci Rep | Volume | 9 |
| Issue | 1 | Pages | 4200 |
| PubMed ID | 30862908 | Mgi Jnum | J:275866 |
| Mgi Id | MGI:6307145 | Doi | 10.1038/s41598-019-41061-z |
| Citation | Girard R, et al. (2019) HNF4alpha is a novel regulator of intestinal glucose-dependent insulinotropic polypeptide. Sci Rep 9(1):4200 |
| abstractText | Mutations in the HNF4A gene cause MODY1 and are associated with an increased risk of Type 2 diabetes mellitus. On the other hand, incretins are hormones that potentiate reductions in blood glucose levels. Given the established role of incretin-based therapy to treat diabetes and metabolic disorders, we investigated a possible regulatory link between intestinal epithelial HNF4alpha and glucose-dependent insulinotropic polypeptide (GIP), an incretin that is specifically produced by gut enteroendocrine cells. Conditional deletion of HNF4alpha in the whole intestinal epithelium was achieved by crossing Villin-Cre and Hnf4alpha(loxP/loxP) C57BL/6 mouse models. GIP expression was measured by qPCR, immunofluorescence and ELISA. Gene transcription was assessed by luciferase and electrophoretic mobility shift assays. Metabolic parameters were analyzed by indirect calorimetry and dual-energy X-ray absorptiometry. HNF4alpha specific deletion in the intestine led to a reduction in GIP. HNF4alpha was able to positively control Gip transcriptional activity in collaboration with GATA-4 transcription factor. Glucose homeostasis and glucose-stimulated insulin secretion remained unchanged in HNF4alpha deficient mice. Changes in GIP production in these mice did not impact nutrition or energy metabolism under normal physiology but led to a reduction of bone area and mineral content, a well described physiological consequence of GIP deficiency. Our findings point to a novel regulatory role between intestinal HNF4alpha and GIP with possible functional impact on bone density. |
