SUN-024 Uncovering a Novel Role for Nuclear Receptor Fxr and Shp in Regulating N-Linked Glycosylation

Abstract

Nuclear receptor Farnesoid X Receptor (Fxr) and Small Heterodimer Partner (Shp) are key regulators of glucose, fat and bile acid homeostasis. As expected, liver-specific deletion of both Fxr and Shp (LDKO) sensitizes mice to bile acid excess. Surprisingly, high throughput RNA-sequencing analysis revealed increases in key glycosyltransferases involved in “decorating” various glycoproteins in LDKO livers. Remarkably, we were able to confirm increased glycan decoration and branching in LDKO livers using glycomics and glycoproteomics approaches. Further, electron microscopic analysis revealed disruption and dilation of Golgi network, which is consistent with aberrant glycosylation. LDKO mice were hypoglycemic, stored lower glycogen, indicating glucose being utilized to meet the increased glycosylation demand. Taken together, we uncover a novel role for hepatic Fxr-Shp axis in maintaining the glycosylation status of proteins in the liver.