Biochemical mechanism of insulin sensitization, lipid modulation and anti-atherogenic potential of PPAR α/γ dual agonist: Ragaglitazar

The current goal in the treatment of diabetes is not only to enhance the glycemic control but also to improve the associated cardiovascular risk factors. Among many of the strategies available, a co-ligand of PPARα and γ in a single molecule which combines the insulin sensitizing potential of PPARγ and the beneficial lipid modulating properties of PPARα agonism, has gained attention in the recent past. Here we report the biochemical mechanism by which a dual PPAR α/γ agonist Ragaglitazar (Raga) achieves this goal. The PPARα component of Raga appears to contribute to a significant increase in beta oxidation, ApoA1 secretion and inhibition of TG biosynthesis in HepG2 cells. These effects of Raga at 60 μM were similar to that shown by Fenofibrate (Feno) at 250 μM. The PPARγ component of Raga showed significant G3PDH activity and TG accumulation with a corresponding increase in aP2 expression in 3T3L1 cells. Significantly reduced levels of IL-6 and TNFα were observed in the culture supernatants of Raga treated 3T3L1 cells. Raga resulted in significant insulin dependent glucose uptake in 3T3L1 with a corresponding increase in GLUT4 expression. Further, Raga showed a significant cholesterol efflux with a corresponding increase in ABCA1 protein expression in THP-1 macrophages. In conclusion, Raga activates both PPARα and γ regulated pathway in adipocytes as well as in hepatocytes which together contributes for its insulin sensitizing and lipid lowering activity. In addition the dual activation of PPAR α/γ also shows an athero-protective potential by inducing reverse cholesterol efflux and inhibiting the pro-inflammatory cytokines.