PPARs (Peroxisome proliferator-activated receptors) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of the following three subtypes: PPARα, PPARγ, and PPARβ/δ. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms. All PPARs heterodimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes. Activation of PPAR-α reduces triglyceride level and is involved in regulation of energy homeostasis. Activation of PPAR-γ enhances glucose metabolism, whereas activation of PPAR-β/δ enhances fatty acids metabolism. Among them, PPARβ/δ is expressed in many tissues, especially in brain, adipose tissue, and skin. In addition, PPARα is a nuclear receptor protein functioning as a transcription factor. PPARα also inhibits glycolysis, while promoting liver gluconeogenesis and glycogen synthesis.

Elafibranor (also known as GFT505) is a potent dual PPARα/δ agonist.

Specifically, Elafibranor shows preferential activity on PPARα (EC50 of 10-20 nM) and additional activity on PPARδ (EC50 of 100-150 nM). Importantly, FDA granted accelerated approval to Elafibranor. Elafibranor has the potential for primary biliary cholangitis research. In addition, Elafibranor is active in disease models of nonalcoholic fatty liver disease (NAFLD)/NASH and liver fibrosis. Elafibranor confers liver protection by acting on several pathways involved in NASH pathogenesis, reducing steatosis, inflammation, and fibrosis. Moreover, in the db/db mouse model of diabetes, Elafibranor regulates glucose homeostasis and plasma lipids in a diabetic model. It improves glycaemic control in db/db mice, including increased hepatic insulin sensitivity and reduced gluconeogenesis. Furthermore, Elafibranor exhibits no PPARγ-related adverse cardiac effects. Besides, long-term Elafibranor administration to monkeys induced no change in haematological parameters or in bone marrow differential cell counts.

To sum up, Elafibranor is a potent dual PPARα/δ agonist that can be used for primary biliary cholangitis and type 2 diabetes research.

[1] Rémy Hanf, et al. Diab Vasc Dis Res. 2014 Nov;11(6):440-7.
[2] Vlad Ratziu, et al. Gastroenterology. 2016 May;150(5):1147-1159.e5.