Glycolytic repression and reduced GLP-1 secretion by active Farnesoid X Receptor in enteroendocrine L cells achieved via PKLR

Summary Rise in intestinal glucose increases GLP-1 secretion by enteroendocrine L cells. GLP-1, in turn, stimulates insulin secretion. Farnesoid X Receptor (FXR) represses this pathway by manipulating the L cell glycolysis, thus reducing insulin- and GLP-1 secretion. The mechanism by which FXR manipulates the L cell glycolysis is unclear. In this study, we construct an L cell specific protein-protein interactome and identify all significantly active protein complexes, inferred by co-expression scores, in FXR-activated and control L cells. Contrary to previous reports, we find extensive glycolytic enzyme activity in FXR-activated L cells. We present how FXR’s repression of the glycolytic enzyme, pyruvate kinase (PKLR), is causing the reduction in glycolytic activity. This mechanistic insight may aid development of drugs targeting the GLP-1 pathway.