Discovery of novel modulators for the PPARα (peroxisome proliferator activated receptor α): Potential therapies for nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a severe liver disease causing serious liver complications, including nonalcoholic steatohepatitis (NASH). Nuclear receptor PPAR alpha (peroxisome proliferator-activated receptor alpha) has drawn special attention recently as a potential developmental drug target to treat type-2 diabetes and related diseases due to its unique functions in regulating lipid metabolism, promoting triglyceride oxidation, and suppressing hepatic inflammation, raising interest in PPAR alpha agonists as potential therapies for NAFLD. However, how PPAR alpha coordinates potential treatment of NAFLD and NASH between various metabolic pathways is still obscure. Here, we show that the DY series of novel selective PPAR alpha modulators activate PPAR alpha by up-regulating PPAR alpha target genes directly involved in NAFLD and NASH. The design, synthesis, docking studies, and in vitro and in vivo evaluation of the novel DY series of PPAR alpha agonists are described.

Automated summary

The study demonstrates that the novel selective PPAR alpha modulators DY series activate PPAR alpha by up-regulating PPAR alpha target genes directly involved in NAFLD and NASH. The design and evaluation of these modulators provide a new approach for the treatment of NAFLD and NASH.