| First Author | Makkar G | Year | 2019 |
| Journal | Am J Physiol Endocrinol Metab | Volume | 317 |
| Issue | 5 | Pages | E794-E804 |
| PubMed ID | 31526288 | Mgi Jnum | J:281554 |
| Mgi Id | MGI:6376930 | Doi | 10.1152/ajpendo.00028.2019 |
| Citation | Makkar G, et al. (2019) Lrrc55 is a novel prosurvival factor in pancreatic islets. Am J Physiol Endocrinol Metab 317(5):E794-E804 |
| abstractText | Pancreatic islets adapt to the increase in insulin demand during pregnancy by upregulating beta-cell number, insulin synthesis, and secretion. These changes require prolactin receptor (PrlR) signaling, as mice with PrlR deletion are glucose intolerant with a lower beta-cell mass. Prolactin also prevents beta-cell apoptosis. Many genes participate in these adaptive changes in the islet, and Lrrc55 is one of the most upregulated genes with unknown function in islets. Because Lrrc55 expression increases in parallel to the increase in beta-cell number and insulin production during pregnancy, we hypothesize that Lrrc55 might regulate beta-cell proliferation/apoptosis (thus beta-cell number) and insulin synthesis. Here, we found that Lrrc55 expression was upregulated by >60-fold during pregnancy in a PrlR-dependent manner, and this increase was restricted only to the islets. Overexpression of Lrrc55 in beta-cells had minimal effect on beta-cell proliferation and glucose-stimulated insulin secretion but protected beta-cells from glucolipotoxicity-induced reduction in insulin gene expression. Moreover, Lrrc55 protects beta-cells from glucolipotoxicity-induced apoptosis, with upregulation of prosurvival signals and downregulation of proapoptotic signals of the endoplasmic reticulum (ER) stress pathway. Furthermore, Lrrc55 attenuated calcium depletion induced by glucolipotoxicity, which may contribute to its antiapoptotic effect. Hence our findings suggest that Lrrc55 is a novel prosurvival factor that is upregulated specifically in islets during pregnancy, and it prevents conversion of adaptive unfolded protein response to unresolved ER stress and apoptosis in beta-cells. Lrrc55 could be a potential therapeutic target in diabetes by reducing ER stress and promoting beta-cell survival. |
