Journal: Therapeutic Advances in Endocrinology and Metabolism

Article Title: GLP-1 receptor agonists and gallbladder disease risk: insights into molecular mechanisms and clinical implications

doi: 10.1177/20420188251406456

Figure Lengend Snippet: Mechanisms linking GLP-1R agonists to gallstone formation. GLP-1RAs suppress CCK secretion, reducing gallbladder contractility and promoting bile retention. They also alter TGR5 signaling, decreasing cAMP-mediated gallbladder relaxation and bile acid-induced GLP-1 secretion. In addition, GLP-1RAs disrupt FXR signaling by reducing FGF19 production, leading to dysregulation of bile acid synthesis and transport through pathways involving cholesterol 7α-hydroxylase (CYP7A1), sterol 12α-hydroxylase (CYP12), and the BSEP. At the neural level, GLP-1RAs activate GLP-1R in the NTS and AP, altering vagal nerve signaling and causing asynchronous contractions of the gallbladder. These combined alterations result in biliary stasis, characterized by prolonged retention of bile and supersaturation with cholesterol, which favors gallstone formation. AP, area postrema; BSEP, bile salt export pump; cAMP, cyclic adenosine monophosphate; CCK, cholecystokinin; FGF19, fibroblast growth factor 19; FXR, farnesoid X receptor; GLP-1RAs, glucagon-like peptide-1 receptor agonists; NTS, nucleus tractus solitaries; TGR5, Takeda G-protein-coupled receptor 5.

Article Snippet: ATP adenosine triphosphate BSEP/ABCB11 bile salt export pump Ca 2+ calcium ions cAMP cyclic adenosine monophosphate CCK cholecystokinin CYP7A1 cholesterol 7α-hydroxylase CYP8B1 sterol 12α-hydroxylase Epac2 exchange protein activated by cAMP-2 FGF19 fibroblast growth factor 19 FGFR4 fibroblast growth factor receptor 4 FXR farnesoid X receptor GLP-1 glucagon-like peptide-1 GLP-1R GLP-1 receptor GLP-1RAs glucagon-like peptide-1 receptor agonists HNF4α hepatocyte nuclear factor 4α IR insulin resistance MASLD metabolically associated steatotic liver disease NTS nucleus of the solitary tract PKA protein kinase A SHP small heterodimer partner T2DM type 2 diabetes mellitus TGR5 Takeda G-protein-coupled receptor 5

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