Combinatorial targeting of GPBAR1 and CYSLTR1 reveals a mechanistic role for bile acids and leukotrienes in drug induced liver injury

Drug induced liver injury (DILI) is a common disorder that involves both direct liver cell toxicity and immune activation. The bile acid receptor GPBAR1 (TGR5) and the cysteinyl leukotriene receptor (CYSLTR)1 are G Protein-Coupled Receptors activated by bile acids and leukotrienes, exerting opposite effects on cell-to-cell adhesion, inflammation and immune cell activation. To investigate whether GPBAR1 and CYSLTR1 mutually interact in development of DILI we have developed an orally active small molecules, CHIN117, that functions as a GPBAR1 agonist and CYSLTR1 antagonist.