Abstract
Osteocalcin is an osteoblast-specific secreted protein that has been associated with endocrine roles in multiple aspects of energy metabolism. We examined whether undercarboxylated osteocalcin (ucOC) downregulates pancreatic lipase (PNLIP) expression in pancreatic acinar cells and then identified the downstream signaling pathway involved. We previously demonstrated that β adrenergic blockade attenuates body weight/fat mass gain in high-fat diet-fed mice and that this effect is associated with decreased PNLIP expression in pancreatic acinar cells. In the present study, we first confirmed that the serum ucOC level is inversely correlated with PNLIP expression, i.e., mice exhibiting high serum levels of ucOC showed low PNLIP levels in the pancreas. In in vitro experiments using primary pancreatic acinar and 266-6 cells, ucOC downregulated PNLIP expression. cAMP/PKA signaling inhibitors significantly reversed ucOC-induced downregulation of PNLIP expression. ucOC promoted the phosphorylation of cAMP response element-binding protein 2 (ATF4). Overexpression of ATF4 significantly suppressed PNLIP expression. Knockdown of ATF4 by siRNA reversed the ucOC-induced downregulation of PNLIP expression. A luciferase reporter assay showed that ucOC suppressed PNLIP promoter transactivation. Chromatin immunoprecipitation and a luciferase reporter assay demonstrated that ATF4 directly bound to the CRE on the mouse PNLIP promoter and suppressed PNLIP transactivation. Knockdown of G-protein coupled receptor 6A (Gprc6a), a candidate receptor for mediating the response to ucOC in the bone-pancreas endocrine loop, by siRNA reversed the downregulating effect of ucOC on PNLIP expression. Taken together, ucOC downregulates pancreatic lipase expression in a cAMP/protein kinase A/ATF4-dependent manner. Gprc6a is a potential osteocalcin-sensing receptor that regulates PNLIP expression in pancreatic acinar cells.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.