Type II diabetes is a complex, chronic, and progressive disease. Glucagon-like peptide-1 (7-36) amide (GLP-1) is a gut hormone released from the L cells which stimulate insulin secretion and promotes insulin gene expression and β-cell growth and differentiation. Elevated levels of hormones secreted by L cells are an essential reason for diabetes improvement. GLP-1 secretion has been reported to be regulated by farnesoid X receptor (FXR), a transcriptional sensor for bile acids which also acts on glucose metabolism. Herein, we attempted to evaluate the effect of FXR on GLP-1 secretion in mouse enteroendocrine L cell line, namely STC-1, and to investigate the underlying mechanism. FXR inversely regulated GLP-1 secretion in STC-1. A total of 24 nonredundant human proteins were shown to be related to FXR by BioGRID; KEGG pathway analysis revealed that FXR was related to glucagon signaling pathway, particularly with the transcriptional activators CREB, PGC1α, Sirt1, and CBP. CREB could positively regulate GLP-1 secretion in STC-1 cells. FXR combined with CREB to inhibit its transcriptional activity, thus inhibiting proprotein convertase subtilisin/kexin type 1 protein level and GLP-1 secretion. In the present study, we demonstrated a negative regulation of GLP-1 secretion by FXR in L cell line, STC-1; FXR exerts its function in L cells through interacting with CREB, a crucial transcriptional regulator of cAMP-CREB signaling pathway, to inhibit its transcriptional activity. Targeting FXR to rescue GLP-1 secretion may be a promising strategy for type II diabetes.
Keywords: Farnesoid X receptor; L cell; glucagon signaling pathway; glucagon-like peptide-1 (7-36) amide; type II diabetes.
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