Seladelpar

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor superfamily with three members - PPAR-alpha (α), PPAR-delta (δ), and PPAR-gamma (γ). Each PPAR plays a role in maintaining energy homeostasis and metabolic function, such as fatty acid metabolism, bile acid synthesis, and adipocyte differentiation. In chronic liver disorders such as PBC and nonalcoholic steatohepatitis (NASH), changes in bile acid composition and increased systemic bile acids are observed.

Seladelpar is a PPAR-delta agonist; however, the mechanism by which seladelpar exerts its therapeutic effects in patients with PBC is not well understood. Pharmacological activity that is potentially relevant to therapeutic effects includes inhibition of bile acid synthesis through activation of PPARδ. Published studies show that PPARδ activation by seladelpar reduces bile acid synthesis through induction of Fibroblast Growth Factor 21 (FGF21) to activate the c-Jun N-terminal kinase (JNK) signalling pathway: This effect subsequently downregulates CYP7A1, the key enzyme for the synthesis of bile acids from cholesterol. It is suggested that the inhibitory effect of seladelpar on bile acid synthesis is independent of the farnesoid X receptor (FXR) pathway, another molecular pathway that regulates bile acid synthesis in the liver.